The Corey-Seebach Reagent in the 21st Century: A Review

The Corey-Seebach reagent plays an important role in organic synthesis because of its broad synthetic applications. The Corey-Seebach reagent is formed by the reaction of an aldehyde or a ketone with 1,3-propane-dithiol under acidic conditions, followed by deprotonation with n-butyllithium. A large variety of natural products (alkaloids, terpenoids, and polyketides) can be accessed successfully by utilizing this reagent. This review article focuses on the recent contributions (post-2006) of the Corey-Seebach reagent towards the total synthesis of natural products such as alkaloids (lycoplanine A, diterpenoid alkaloids, etc.), terpenoids (bisnorditerpene, totarol, etc.), polyketide (ambruticin J, biakamides, etc.), and heterocycles such as rodocaine and substituted pyridines, as well and their applications towards important organic synthesis.


Introduction
Elias James Corey is an American chemist well-known for his contribution to the development of methodology and theory of organic synthesis, especially retrosynthetic analysis. He was awarded a Nobel Prize in 1990 for the development of retrosynthetic analysis. His research cooperation with other famous organic chemists has resulted in various name reactions, based on his name, in organic chemistry [1]. One of his famous reactions is the Corey-Seebach reaction which was a combined work of Corey and Dieter Seebach (a German chemist). The Corey-Seebach reagent is formed by the reaction of an aldehyde or a ketone with 1,3-propane-dithiol in the presence of acidic conditions (Lewis acid). Corey-Seebach is a nucleophilic moiety and has widespread applications in various organic transformations. This reaction was first published in 1965, which reported the synthesis of dicarbonyl derivative from 1,3-dithiane [2]. This acyl anion intermediate easily provides access to α-hydroxy ketones [3][4][5][6] by reacting with a range of electrophiles, including carbonyl compounds ( Figure 1) [7]. In order to regenerate the carbonyl group that was initially masked when dithiane was utilized as an acyl anion equivalent, it must be hydrolyzed at some point during synthesis. Deprotection has frequently been challenging to accomplish, especially for complicated and sensitive compounds, and as a result, numerous processes have been adopted. The use of traditional methods such as metal salts (mercury(II) chloride [8]) for the deprotection of 1,3-dithiane requires toxic reagents that are generally harmful to the environment. However, there are some facile and efficient methods available in the literature, i.e., 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) deprotection [9] and the use of iodine catalyst/H2O2 [10] which are more environment friendly.
In a typical 1,3-dithiane addition process, 1,3-dithiane is combined with an equimolar quantity of a strong base, such as n-butyllithium, and the resultant 2-lithio-1,3-dithiane should serve as an appropriate nucleophile. According to a different procedure described by Andersen et al. [11] the 1,3-dithiane equivalent, 2-trimethylsilyl-1,3-dithiane (TMS-dithiane), could be activated by a stoichiometric quantity of tetrabutylammonium fluoride (TBAF), resulting in the matching carbanion. Corey et al. claim that various cesium salt mixtures that include cesium fluoride may be used as heterogeneous desilylating reagents. There are just a few cases when TMS-dithiane has been activated catalytically, and most of these reactions involve the use of fluoride reagents in equimolar amounts [12].
The Corey-Seebach umpolung technique has been extensively utilized to manufacture a wide variety of natural products such as Swinholide A [13] (1, a marine natural product, derived from sponge Theonella swinhoei, which shows antitumor and antifungal activity), pironetin [14][15][16] (2, derived from Streptomyces fermentation broths, which exhibits plant growth regulating action) (Figure 2), ciguatoxin 1B [17] (3, one of the main toxins responsible for ciguatera fish poisoning (Figure 3), discovered from moray eel Gymnothorax javanicus), and maytansine [18,19] (4, shows antitumor activity) ( Figure 4). Many synthetic [20] compounds, such as photolabile safety benzoin linkers [21] and bis-3,4-dihydroisoquinolium salts [22], have also been attained using the Corey-Seebach reagent. Earlier, Foubelo et al. published a review article in 2003 concerning the use of 1,3-dithianes in the synthesis of natural products [23]. Until now, the Corey-Seebach reagent has found valuable applications in organic synthesis. Our review article focuses on the utilization of Corey-Seebach reagent in the synthesis of noteworthy natural and synthetic organic compounds reported post-2006.  In order to regenerate the carbonyl group that was initially masked when dithiane was utilized as an acyl anion equivalent, it must be hydrolyzed at some point during synthesis. Deprotection has frequently been challenging to accomplish, especially for complicated and sensitive compounds, and as a result, numerous processes have been adopted. The use of traditional methods such as metal salts (mercury(II) chloride [8]) for the deprotection of 1,3-dithiane requires toxic reagents that are generally harmful to the environment. However, there are some facile and efficient methods available in the literature, i.e., 2,3-dichloro-5,6dicyano-1,4-benzoquinone (DDQ) deprotection [9] and the use of iodine catalyst/H 2 O 2 [10] which are more environment friendly.
In a typical 1,3-dithiane addition process, 1,3-dithiane is combined with an equimolar quantity of a strong base, such as n-butyllithium, and the resultant 2-lithio-1,3-dithiane should serve as an appropriate nucleophile. According to a different procedure described by Andersen et al. [11] the 1,3-dithiane equivalent, 2-trimethylsilyl-1,3-dithiane (TMSdithiane), could be activated by a stoichiometric quantity of tetrabutylammonium fluoride (TBAF), resulting in the matching carbanion. Corey et al. claim that various cesium salt mixtures that include cesium fluoride may be used as heterogeneous desilylating reagents. There are just a few cases when TMS-dithiane has been activated catalytically, and most of these reactions involve the use of fluoride reagents in equimolar amounts [12].
The Corey-Seebach umpolung technique has been extensively utilized to manufacture a wide variety of natural products such as Swinholide A [13] (1, a marine natural product, derived from sponge Theonella swinhoei, which shows antitumor and antifungal activity), pironetin [14][15][16] (2, derived from Streptomyces fermentation broths, which exhibits plant growth regulating action) (Figure 2), ciguatoxin 1B [17] (3, one of the main toxins responsible for ciguatera fish poisoning (Figure 3), discovered from moray eel Gymnothorax javanicus), and maytansine [18,19] (4, shows antitumor activity) ( Figure 4). Many synthetic [20] compounds, such as photolabile safety benzoin linkers [21] and bis-3,4dihydroisoquinolium salts [22], have also been attained using the Corey-Seebach reagent. Earlier, Foubelo et al. published a review article in 2003 concerning the use of 1,3-dithianes in the synthesis of natural products [23]. Until now, the Corey-Seebach reagent has found valuable applications in organic synthesis. Our review article focuses on the utilization of Corey-Seebach reagent in the synthesis of noteworthy natural and synthetic organic compounds reported post-2006. In order to regenerate the carbonyl group that was initially masked when dithiane was utilized as an acyl anion equivalent, it must be hydrolyzed at some point during synthesis. Deprotection has frequently been challenging to accomplish, especially for complicated and sensitive compounds, and as a result, numerous processes have been adopted. The use of traditional methods such as metal salts (mercury(II) chloride [8]) for the deprotection of 1,3-dithiane requires toxic reagents that are generally harmful to the environment. However, there are some facile and efficient methods available in the literature, i.e., 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) deprotection [9] and the use of iodine catalyst/H2O2 [10] which are more environment friendly.
In a typical 1,3-dithiane addition process, 1,3-dithiane is combined with an equimolar quantity of a strong base, such as n-butyllithium, and the resultant 2-lithio-1,3-dithiane should serve as an appropriate nucleophile. According to a different procedure described by Andersen et al. [11] the 1,3-dithiane equivalent, 2-trimethylsilyl-1,3-dithiane (TMS-dithiane), could be activated by a stoichiometric quantity of tetrabutylammonium fluoride (TBAF), resulting in the matching carbanion. Corey et al. claim that various cesium salt mixtures that include cesium fluoride may be used as heterogeneous desilylating reagents. There are just a few cases when TMS-dithiane has been activated catalytically, and most of these reactions involve the use of fluoride reagents in equimolar amounts [12].

Lycoplanine A Alkaloids
Lycopodium alkaloids are known to play an effective role in the medication of Alzheimer's disease [24][25][26]. Over 300 lycopodium alkaloids have so far been isolated, and a number of total syntheses of these alkaloids have been published [27][28][29]. In 2017, Zhao and co-workers [30] first isolated lycoplanine A, a lycopodium alkaloid with the γ-lactone ring. According to biological investigations, lycoplanine alkaloid is a strong inhibitor of the calcium channel (Cav3.1 T-type) with an IC50 value of 6.06 μM. In 2021, Gao et al. [31] reported the synthesis of lycoplanine A isomer by utilizing the Corey-Seebach reagent. To achieve this task, the C=C bond was introduced by using 1,4-dithiane 5 and crotonaldehyde (E/Z > 98%) to afford alcohol 6 in an 88% yield, followed by oxidation to provide the product 7 with an 80% yield. Compound 7 was then treated with Nysted reagent for the introduction of the second C=C, followed by the introduction of fragment A to afford compound 8 by using the Mitsunobu reaction. After a few steps, compound 9 was formed, which upon reaction with Crabtree's catalyst provided a tetrasubstituted C=C bond product 10 with excellent stereo and regioselectivities. After deprotection of the Boc group, compound 10 was immediately exposed to AcOH, initiating a cascade reaction that produced the stereo-specific cyclized product 11 with a 35% yield. The deprotection of the thioketal group was achieved by using PIFA to afford lycoplanine A 12 isomer with an 83% yield (Scheme 1).

Lycoplanine A Alkaloids
Lycopodium alkaloids are known to play an effective role in the medication of Alzheimer's disease [24][25][26]. Over 300 lycopodium alkaloids have so far been isolated, and a number of total syntheses of these alkaloids have been published [27][28][29]. In 2017, Zhao and co-workers [30] first isolated lycoplanine A, a lycopodium alkaloid with the γ-lactone ring. According to biological investigations, lycoplanine alkaloid is a strong inhibitor of the calcium channel (Cav3.1 T-type) with an IC50 value of 6.06 μM. In 2021, Gao et al. [31] reported the synthesis of lycoplanine A isomer by utilizing the Corey-Seebach reagent. To achieve this task, the C=C bond was introduced by using 1,4-dithiane 5 and crotonaldehyde (E/Z > 98%) to afford alcohol 6 in an 88% yield, followed by oxidation to provide the product 7 with an 80% yield. Compound 7 was then treated with Nysted reagent for the introduction of the second C=C, followed by the introduction of fragment A to afford compound 8 by using the Mitsunobu reaction. After a few steps, compound 9 was formed, which upon reaction with Crabtree's catalyst provided a tetrasubstituted C=C bond product 10 with excellent stereo and regioselectivities. After deprotection of the Boc group, compound 10 was immediately exposed to AcOH, initiating a cascade reaction that produced the stereo-specific cyclized product 11 with a 35% yield. The deprotection of the thioketal group was achieved by using PIFA to afford lycoplanine A 12 isomer with an 83% yield (Scheme 1). Lycopodium alkaloids are known to play an effective role in the medication of Alzheimer's disease [24][25][26]. Over 300 lycopodium alkaloids have so far been isolated, and a number of total syntheses of these alkaloids have been published [27][28][29]. In 2017, Zhao and co-workers [30] first isolated lycoplanine A, a lycopodium alkaloid with the γ-lactone ring. According to biological investigations, lycoplanine alkaloid is a strong inhibitor of the calcium channel (C av 3.1 T-type) with an IC 50 value of 6.06 µM. In 2021, Gao et al. [31] reported the synthesis of lycoplanine A isomer by utilizing the Corey-Seebach reagent. To achieve this task, the C=C bond was introduced by using 1,4-dithiane 5 and crotonaldehyde (E/Z > 98%) to afford alcohol 6 in an 88% yield, followed by oxidation to provide the product 7 with an 80% yield. Compound 7 was then treated with Nysted reagent for the introduction of the second C=C, followed by the introduction of fragment A to afford compound 8 by using the Mitsunobu reaction. After a few steps, compound 9 was formed, which upon reaction with Crabtree's catalyst provided a tetrasubstituted C=C bond product 10 with excellent stereo and regioselectivities. After deprotection of the Boc group, compound 10 was immediately exposed to AcOH, initiating a cascade reaction that produced the stereo-specific cyclized product 11 with a 35% yield. The deprotection of the thioketal group was achieved by using PIFA to afford lycoplanine A 12 isomer with an 83% yield (Scheme 1). Scheme 1. Synthesis of lycoplanine A 12 isomer via Corey-Seebach reagent.

Diterpenoid Alkaloids
Diterpenoid alkaloids have been the focus of study by scientists all over the globe because of their fascinating bioactivities and complicated structures [32]. These biologically active compounds were extracted from Delphinium and Aconitum species that belong to the Ranunculaceae family [33]. In 2017, Min Zhu et al. [34] reported the synthesis of hetidine-type C20-diterpenoid alkaloids by utilizing the Corey-Seebach reagent as a key step. For this purpose, 2-lithio-1,3-dithiane species 14 were reacted with iodide 13, followed by the deprotection of methoxymethyl to afford olefinic phenol 15 with an 80% yield. In the next step, compound 15 was treated with PhI(OAc)2, followed by the addition of Sml2 to obtain compound 16, which could then be transformed into the desired hetidine-type diterpenoid alkaloid 17 after a series of reactions (Scheme 2).

Diterpenoid Alkaloids
Diterpenoid alkaloids have been the focus of study by scientists all over the globe because of their fascinating bioactivities and complicated structures [32]. These biologically active compounds were extracted from Delphinium and Aconitum species that belong to the Ranunculaceae family [33]. In 2017, Min Zhu et al. [34] reported the synthesis of hetidinetype C 20 -diterpenoid alkaloids by utilizing the Corey-Seebach reagent as a key step. For this purpose, 2-lithio-1,3-dithiane species 14 were reacted with iodide 13, followed by the deprotection of methoxymethyl to afford olefinic phenol 15 with an 80% yield. In the next step, compound 15 was treated with PhI(OAc) 2 , followed by the addition of Sml 2 to obtain compound 16, which could then be transformed into the desired hetidine-type diterpenoid alkaloid 17 after a series of reactions (Scheme 2).

Diterpenoid Alkaloids
Diterpenoid alkaloids have been the focus of study by scientists all over the globe because of their fascinating bioactivities and complicated structures [32]. These biologically active compounds were extracted from Delphinium and Aconitum species that belong to the Ranunculaceae family [33]. In 2017, Min Zhu et al. [34] reported the synthesis of hetidine-type C20-diterpenoid alkaloids by utilizing the Corey-Seebach reagent as a key step. For this purpose, 2-lithio-1,3-dithiane species 14 were reacted with iodide 13, followed by the deprotection of methoxymethyl to afford olefinic phenol 15 with an 80% yield. In the next step, compound 15 was treated with PhI(OAc)2, followed by the addition of Sml2 to obtain compound 16, which could then be transformed into the desired hetidine-type diterpenoid alkaloid 17 after a series of reactions (Scheme 2).

Bisnorditerpene
Diterpenoids are important natural products that display a wide range of chemical diversity and are useful both in medicine and industry. A large number of known diterpenoid compounds are isolated from plants and fungi, and investigations into these species have provided an understanding of their production [35]. In 2010, Pessoa et al. [36] first isolated a bisnorditerpene from Croton regelianus var. matosii. This herb is utilized in traditional medicine in the Northeastern state of "Caatinga". In 2016, Xu et al. [37] designed a new strategy for the synthesis of bisnorditerpene by utilizing the Corey-Seebach reagent. To achieve this, an aldehyde 18 was allowed to react with 1,3-propane-dithiol 19 to furnish dithiane 20, which upon lithiation with epoxide [38] 21 by using the Corey-Seebach reaction afforded precursor 22 followed by the addition of Lewis acid to obtain tricyclic alcohol 23 with a 55% yield. In the next step, secondary alcohol 24 was obtained by desulfurization of 23 with Raney-Ni, followed by the oxidation of 24 with Dess-Martin periodinane (DMP) to afford ketone 25 with a 95% yield. The final process involved the demethylation of ketone 25 with BBr 3 along with the addition of Phl(OAc) 2 in CH 3 CN to generate bisnorditerpene 26 (Scheme 3).

Bisnorditerpene
Diterpenoids are important natural products that display a wide range of chemical diversity and are useful both in medicine and industry. A large number of known diterpenoid compounds are isolated from plants and fungi, and investigations into these species have provided an understanding of their production [35]. In 2010, Pessoa et al. [36] first isolated a bisnorditerpene from Croton regelianus var. matosii. This herb is utilized in traditional medicine in the Northeastern state of "Caatinga". In 2016, Xu et al. [37] designed a new strategy for the synthesis of bisnorditerpene by utilizing the Corey-Seebach reagent. To achieve this, an aldehyde 18 was allowed to react with 1,3-propane-dithiol 19 to furnish dithiane 20, which upon lithiation with epoxide [38] 21 by using the Corey-Seebach reaction afforded precursor 22 followed by the addition of Lewis acid to obtain tricyclic alcohol 23 with a 55% yield. In the next step, secondary alcohol 24 was obtained by desulfurization of 23 with Raney-Ni, followed by the oxidation of 24 with Dess-Martin periodinane (DMP) to afford ketone 25 with a 95% yield. The final process involved the demethylation of ketone 25 with BBr3 along with the addition of Phl(OAc)2 in CH3CN to generate bisnorditerpene 26 (Scheme 3).

Totarol Synthesis
Totarol belongs to diterpenes that are found in the sap of podocarpus totara, a New Zealand native conifer [39]. The antimicrobial properties [40][41][42][43] of the secondary metabolites in this sap are well known. The wood of this tree displays resistance against rot. Toothpaste and acne medications are just a couple of consumer goods that can contain totarol as an antibacterial ingredient. In 2010, Kim et al. [44] synthesized totarol by utilizing the Corey-Seebach approach as an important key step. The goal of their research was to synthesize totarol diterpenes as a part of a larger research project to determine the mechanism by which tiny molecules could inactivate FtsZ. In order to achieve this, benzonitrile 27 was treated with i-PrMgCl to produce compound 28, followed by the reduction and thioacetal formation to obtain product 29. In the next step, alkene 30 was synthesized through lithiation of 29 with fragment B followed by alkylation, respectively. Treatment of compound 30 with AD-mix-β afforded regio-isomeric diol 31 with 90-95% enantiomeric excess, and after a few steps, totarolone 32 was formed with a 33% yield. Totarolone 32 was transformed into the desired totarol 33 through the Wolff-Kishner reduction (Scheme 4).

Totarol Synthesis
Totarol belongs to diterpenes that are found in the sap of podocarpus totara, a New Zealand native conifer [39]. The antimicrobial properties [40][41][42][43] of the secondary metabolites in this sap are well known. The wood of this tree displays resistance against rot. Toothpaste and acne medications are just a couple of consumer goods that can contain totarol as an antibacterial ingredient. In 2010, Kim et al. [44] synthesized totarol by utilizing the Corey-Seebach approach as an important key step. The goal of their research was to synthesize totarol diterpenes as a part of a larger research project to determine the mechanism by which tiny molecules could inactivate FtsZ. In order to achieve this, benzonitrile 27 was treated with i-PrMgCl to produce compound 28, followed by the reduction and thioacetal formation to obtain product 29. In the next step, alkene 30 was synthesized through lithiation of 29 with fragment B followed by alkylation, respectively. Treatment of compound 30 with AD-mix-β afforded regio-isomeric diol 31 with 90-95% enantiomeric excess, and after a few steps, totarolone 32 was formed with a 33% yield. Totarolone 32 was transformed into the desired totarol 33 through the Wolff-Kishner reduction (Scheme 4).

Ambruticin J Synthesis
A significant class of polyketide-based natural compounds known as ambruticin was initially isolated from the bacterium Sorangium cellulosum in 1977. They display high biological advantages such as strong antifungal action [45][46][47][48][49][50]. The mechanistic studies of these compounds suggested that ambruticins target Hik1 kinase [51,52] by interacting with fungal osmoregulation. The influence of ambruticin VS3 on soil myxobacteria has recently been studied, and results showed that they are beneficial for the environment by preventing the emergence of antagonistic myxobacterial species. In 2021, Trentadue et al. [53] reported the total synthesis of ambruticin J by utilizing the Corey-Seebach reagent as a key step. For this purpose, dithiane 34 (synthesized from propargyl alcohol) was reacted with epoxide 35 by using the Corey-Seebach reaction to afford compound 36 with a 70% yield, and after a few steps, vinyl iodide 37 was formed. In the following stage, vinyl iodide 37 reacted with pinacol boronic ester 38 through Suzuki coupling, followed by oxidation using Dess-Martin periodinane (DMP) to afford aldehyde 39. The aldehyde 39 was further treated with fragment C via Julia-Kocienski olefination to afford E-olefin 40, and after a few steps, the desired ambruticin J 41 was formed (Scheme 5).

Ambruticin J Synthesis
A significant class of polyketide-based natural compounds known as ambruticin was initially isolated from the bacterium Sorangium cellulosum in 1977. They display high biological advantages such as strong antifungal action [45][46][47][48][49][50]. The mechanistic studies of these compounds suggested that ambruticins target Hik1 kinase [51,52] by interacting with fungal osmoregulation. The influence of ambruticin VS3 on soil myxobacteria has recently been studied, and results showed that they are beneficial for the environment by preventing the emergence of antagonistic myxobacterial species. In 2021, Trentadue et al. [53] reported the total synthesis of ambruticin J by utilizing the Corey-Seebach reagent as a key step. For this purpose, dithiane 34 (synthesized from propargyl alcohol) was reacted with epoxide 35 by using the Corey-Seebach reaction to afford compound 36 with a 70% yield, and after a few steps, vinyl iodide 37 was formed. In the following stage, vinyl iodide 37 reacted with pinacol boronic ester 38 through Suzuki coupling, followed by oxidation using Dess-Martin periodinane (DMP) to afford aldehyde 39. The aldehyde 39 was further treated with fragment C via Julia-Kocienski olefination to afford E-olefin 40, and after a few steps, the desired ambruticin J 41 was formed (Scheme 5).

Biakamides
Biakamides are naturally occurring polyketides with significant biological activity [54,55]. In 2017, Kotoku et al. [56] first isolated biakamides from a marine sponge Petrosaspongia sp. The purpose of this research project was to isolate marine-based anticancer drugs. To achieve this, marine-based biakamides were isolated, and the total synthesis of these drugs has also been described by using the Corey-Seebach reaction in one of their key steps. The synthesis was initiated by using substituted penta-diol 42, which was converted into corresponding Weinreb amide 43, followed by reduction with DIBAL to obtain compound 44. Aldehyde 44 was treated with 1,3-propane dithiol in the presence of iodine to afford 1,3-dithiane 45. Compound 45 was then allowed to react with alkyl iodide 46 in the presence of n-BuLi by using the Corey-Seebach reaction followed by TBAF addition and subsequent tetrapropylammonium perruthenate (TPAP) oxidation to furnish aldehyde 47. After a few steps, N-methyle-neamide 48 was synthesized from secondary amine 49, followed by the deprotection of 1,3-dithiane to provide compound 50. The chloromethylene moiety was introduced in the presence of (chloromethyl)triphenyl-phosphonium chloride with E/Z 3:2 by using the Wittig reaction, which resulted in compound 51. In the last step, TFA was used for the deprotection of the amine, followed by a condensation reaction with E-3-methoxy-2-butenoic acid 52 to afford (4R, 6S)-biakamides 53 and 54 (Scheme 6). The antiproliferative activity of biakamides 53 and 54 was also examined against PANC-1 cell culture (glucose deficient conditions), which provided an IC 50 value of 0.5 µM.

Bisacyldigermanes
The synthesis of improved photoinitiator molecules for free radical polymerization has been a challenging task. So far, a large number of photoinitiators, such as acyl-phosphine oxides, have been successfully synthesized [57]. Among all types, germanium-based photoinitiators are of great importance due to their non-toxic behavior and excellent bleaching properties [58]. In 2022, Wiesner et al. [59] synthesized bisacyldigermanes 59 by utilizing the Corey-Seebach reaction. The purpose of this synthesis was to introduce double germanium content in order to achieve a higher polymerization rate. For this purpose, 1,2-dichloro-1,1,2,2-tetraethyldi-germane 56 was synthesized over four steps from diethyl dichloro germane 55, followed by lithiation with thioketals 57a-e to afford germane derivatives 58a-e. In the last step, compounds 58a-e were deprotected and oxidized using boron trifluoride etherate and (diacetoxyiodo)benzene (PIDA) to obtain bisacyldigermanes 59a-e in good yields (Scheme 7).

Biakamides
Biakamides are naturally occurring polyketides with significant biological act [54,55]. In 2017, Kotoku et al. [56] first isolated biakamides from a marine sponge P saspongia sp. The purpose of this research project was to isolate marine-based anti-ca drugs. To achieve this, marine-based biakamides were isolated, and the total synthes

Bisacyldigermanes
The synthesis of improved photoinitiator molecules for free radical polymerizat has been a challenging task. So far, a large number of photoinitiators, such as acyl-ph phine oxides, have been successfully synthesized [57]. Among all types, germaniu derivatives 58a-e. In the last step, compounds 58a-e were deprotected and oxidized using boron trifluoride etherate and (diacetoxyiodo)benzene (PIDA) to obtain bisacyldigermanes 59a-e in good yields (Scheme 7).

Benzoylgermanium Derivatives
Germanium-based photoinitiators have attained great importance due to their high radical polymerization capacity [60,61]. In 2009, Moszner et al. [62] synthesized benzoyl germanium derivatives using the Corey-Seebach reaction. These benzoyl germanium derivatives are used in dental cements and composites. In the first step, aromatic 1,3-dithianes 59 were reacted with n-BuLi by using the Corey-Seebach reaction, followed by the reaction with dichlorogermanium compound 60 to afford compound 61a-f. In the last step, compound 61 was dithioketolized in the presence of BF3 . OEt2 and Phl(OAc)2 or in the presence of excess iodine and CaCO3 in THF to provide PIs 62a-f (Scheme 8).

Benzoylgermanium Derivatives
Germanium-based photoinitiators have attained great importance due to their high radical polymerization capacity [60,61]. In 2009, Moszner et al. [62] synthesized benzoyl germanium derivatives using the Corey-Seebach reaction. These benzoyl germanium derivatives are used in dental cements and composites. In the first step, aromatic 1,3dithianes 59 were reacted with n-BuLi by using the Corey-Seebach reaction, followed by the reaction with dichlorogermanium compound 60 to afford compound 61a-f. In the last step, compound 61 was dithioketolized in the presence of BF 3 ·OEt 2 and Phl(OAc) 2 or in the presence of excess iodine and CaCO 3 in THF to provide PIs 62a-f (Scheme 8).

Benzoylgermanium Derivatives
Germanium-based photoinitiators have attained great importance due to their high radical polymerization capacity [60,61]. In 2009, Moszner et al. [62] synthesized benzoyl germanium derivatives using the Corey-Seebach reaction. These benzoyl germanium derivatives are used in dental cements and composites. In the first step, aromatic 1,3-dithianes 59 were reacted with n-BuLi by using the Corey-Seebach reaction, followed by the reaction with dichlorogermanium compound 60 to afford compound 61a-f. In the last step, compound 61 was dithioketolized in the presence of BF3 . OEt2 and Phl(OAc)2 or in the presence of excess iodine and CaCO3 in THF to provide PIs 62a-f (Scheme 8).

Photoinduced Sensitization
The dithiane-based adducts have been found to be suitable candidates for photoinduced fragmentation [63]. The cleavage of dithiane has been studied by physical ap-proaches such as kinetic isotopic effect [64], Hammett substituent effect, and laser flash photolysis studies [65]. In 2006, Gustafson et al. [66] synthesized benzophenone adducts by utilizing the Corey-Seebach reaction. They also studied computational mechanisms for photoinduced cleavage of dithiane-based benzophenone. For this purpose, the dithianes 63a-e were reacted with benzophenone 64 through the Corey-Seebach reaction to furnish dithiane-based benzophenone adducts 65a-e, followed by photoinduced fragmentation in a temperature range of −40 • C-40 • C (Scheme 9).

Photoinduced Sensitization
The dithiane-based adducts have been found to be suitable candidates for photoinduced fragmentation [63]. The cleavage of dithiane has been studied by physical approaches such as kinetic isotopic effect [64], Hammett substituent effect, and laser flash photolysis studies [65]. In 2006, Gustafson et al. [66] synthesized benzophenone adducts by utilizing the Corey-Seebach reaction. They also studied computational mechanisms for photoinduced cleavage of dithiane-based benzophenone. For this purpose, the dithianes 63a-e were reacted with benzophenone 64 through the Corey-Seebach reaction to furnish dithiane-based benzophenone adducts 65a-e, followed by photoinduced fragmentation in a temperature range of −40 °C-40 °C (Scheme 9). Scheme 9. Synthesis of benzophenone adducts 65a−e by utilizing Corey-Seebach reaction.

Photoinduced Bis-Addition
The Corey-Seebach methodology, which is built on lithiodithiane reactions with various electrophiles, particularly carbonyl compounds, has taken a leading position among many of the traditional modern synthetic chemistry strategies [67]. One of its variants, the methyl dithiane addition with benzoyl chloride or alkyl benzoates, provides access to tertiary alcohols with two dithiane moieties [68]. Valiulin et al. [69] reported a synthesis of dithiane adducts by using the Corey-Seebach reaction. The methodology involved the reaction of alkyl dithiane methyl benzoate or benzoyl chloride to afford the target molecule. It was observed that the dithiane adduct 67 was only formed when methyl-containing benzoyl dithiane 66 was used. The acetophenone tethered thio-ortho ester 68 was formed when the R group with the higher substitution was used (Scheme 10).

Photoinduced Bis-Addition
The Corey-Seebach methodology, which is built on lithiodithiane reactions with various electrophiles, particularly carbonyl compounds, has taken a leading position among many of the traditional modern synthetic chemistry strategies [67]. One of its variants, the methyl dithiane addition with benzoyl chloride or alkyl benzoates, provides access to tertiary alcohols with two dithiane moieties [68]. Valiulin et al. [69] reported a synthesis of dithiane adducts by using the Corey-Seebach reaction. The methodology involved the reaction of alkyl dithiane methyl benzoate or benzoyl chloride to afford the target molecule. It was observed that the dithiane adduct 67 was only formed when methyl-containing benzoyl dithiane 66 was used. The acetophenone tethered thio-ortho ester 68 was formed when the R group with the higher substitution was used (Scheme 10).

Photoinduced Sensitization
The dithiane-based adducts have been found to be suitable candidates for photoinduced fragmentation [63]. The cleavage of dithiane has been studied by physical approaches such as kinetic isotopic effect [64], Hammett substituent effect, and laser flash photolysis studies [65]. In 2006, Gustafson et al. [66] synthesized benzophenone adducts by utilizing the Corey-Seebach reaction. They also studied computational mechanisms for photoinduced cleavage of dithiane-based benzophenone. For this purpose, the dithianes 63a-e were reacted with benzophenone 64 through the Corey-Seebach reaction to furnish dithiane-based benzophenone adducts 65a-e, followed by photoinduced fragmentation in a temperature range of −40 °C-40 °C (Scheme 9). Scheme 9. Synthesis of benzophenone adducts 65a−e by utilizing Corey-Seebach reaction.

Photoinduced Bis-Addition
The Corey-Seebach methodology, which is built on lithiodithiane reactions with various electrophiles, particularly carbonyl compounds, has taken a leading position among many of the traditional modern synthetic chemistry strategies [67]. One of its variants, the methyl dithiane addition with benzoyl chloride or alkyl benzoates, provides access to tertiary alcohols with two dithiane moieties [68]. Valiulin et al. [69] reported a synthesis of dithiane adducts by using the Corey-Seebach reaction. The methodology involved the reaction of alkyl dithiane methyl benzoate or benzoyl chloride to afford the target molecule. It was observed that the dithiane adduct 67 was only formed when methyl-containing benzoyl dithiane 66 was used. The acetophenone tethered thio-ortho ester 68 was formed when the R group with the higher substitution was used (Scheme 10).

Bisbibenzyl Analogue Riccardin C Synthesis
Bisbibenzyls are important natural products that are found in the bryophytes, such as liverworts [70][71][72]. Among these, riccardin C has gained great importance due to its effectiveness against cardiovascular diseases. Riccardin C also shows antifungal [73], antibacterial, and cytotoxic activity [74]. In 2016, Almalki et al. [75] purposed the total synthesis of riccardin C by using the Corey-Seebach macrocyclization strategy. For this purpose, compound 70 was synthesized from catechol 69 over a few steps, followed by the reaction of compounds 70 and 71 via Suzuki-Miyaura coupling to obtain compound 72. Further, compounds 73 and 74 were reacted to form biaryl ethers 75, followed by coupling with aldehydes 75 and alcohol 72 to afford compound 76. Compound 76 was transformed into 77 by the Heck reaction followed by the reduction of alkene using diimide. Next, SOCl 2 or MsCl was used to convert the alcohol into chloride 78. In the last step, dithiane was deprotonated by using n-BuLi at 78 • C and the Corey-Seebach reaction to afford macrocycle 79, followed by the deprotection of benzyl ether and dithiane to achieve riccardin C 80 (Scheme 11).

Riccardin C Synthesis
Bisbibenzyls are important natural products that are found in the bryophytes, such as liverworts [70][71][72]. Among these, riccardin C has gained great importance due to its effectiveness against cardiovascular diseases. Riccardin C also shows antifungal [73], antibacterial, and cytotoxic activity [74]. In 2016, Almalki et al. [75] purposed the total synthesis of riccardin C by using the Corey-Seebach macrocyclization strategy. For this purpose, compound 70 was synthesized from catechol 69 over a few steps, followed by the reaction of compounds 70 and 71 via Suzuki-Miyaura coupling to obtain compound 72. Further, compounds 73 and 74 were reacted to form biaryl ethers 75, followed by coupling with aldehydes 75 and alcohol 72 to afford compound 76. Compound 76 was transformed into 77 by the Heck reaction followed by the reduction of alkene using diimide. Next, SOCl2 or MsCl was used to convert the alcohol into chloride 78. In the last step, dithiane was deprotonated by using n-BuLi at 78 °C and the Corey-Seebach reaction to afford macrocycle 79, followed by the deprotection of benzyl ether and dithiane to achieve riccardin C 80 (Scheme 11).

Benzoin-Derived Diol Linker
The synthesis of photodegradable biocompatible polymers has created a serious problem due to their slow degradation and unwanted by-products. Such restrictions may be overcome by using dithiane-protected benzoin derivatives [76,77]. In 2018, Englert et al. [78] synthesized diol benzoin derivatives that act as active monomers for the polymerization process. The main focus of this study was to synthesize micro and nanoparticles that may release compounds on demand within predetermined time frames when "opened" by UV radiation. For this purpose, a diol precursor 82 was synthesized from 3-hydroxybenzaldehyde 81 in three steps by using the Corey-Seebach reaction. In the next step, product 82 was activated to obtain compound 83 or by the reaction of butyryl chloride with compound 82 to afford product 84 prior to activation. In the last step, the polymerization of compound 83 was done with adipoyl dichloride to attain polyester 85 through polycondensation (Scheme 12).

Biocompatible Polyesters
Benzoin-Derived Diol Linker The synthesis of photodegradable biocompatible polymers has created a serious problem due to their slow degradation and unwanted by-products. Such restrictions may be overcome by using dithiane-protected benzoin derivatives [76,77]. In 2018, Englert et al. [78] synthesized diol benzoin derivatives that act as active monomers for the polymerization process. The main focus of this study was to synthesize micro and nanoparticles that may release compounds on demand within predetermined time frames when "opened" by UV radiation. For this purpose, a diol precursor 82 was synthesized from 3hydroxybenzaldehyde 81 in three steps by using the Corey-Seebach reaction. In the next step, product 82 was activated to obtain compound 83 or by the reaction of butyryl chloride with compound 82 to afford product 84 prior to activation. In the last step, the polymerization of compound 83 was done with adipoyl dichloride to attain polyester 85 through polycondensation (Scheme 12).

Scleropentaside A
Scleropentasides are a prime class of natural products that have been extracted from the twigs, leaves, and stems of dendrotrophe frutescens and scleropyrum pentadrum [82], respectively. Both plants exhibit a variety of uses in traditional Asian medicine, including skin treatments, rheumatic pain relief, etc. This innovative class of natural compounds has an unrivaled anomeric-β-glycosidic motif and a furan ring [83]. One of the most iconic members of this class is scleropentaside A, which displays a radical scavenging activity. Boehlich et al. [84] reported an exclusive and general method for the preparation of acylglycosides by utilizing the Corey-Seebach reaction. This methodology has been exclusively used for the short synthesis of scleropentaside A. For this purpose, a silane-protected carbohydrate 90 was reacted with furfural dithiane 91 to obtain product 92, which upon deprotection, afforded sceropentaside A 93 with a good yield (Scheme 14).

Withanolide A
One of the most potent components in the methanolic extracts of ashwagandha is withanolide A, which was isolated from the roots of Withania somnifera [85]. It has been shown to have strong pharmacological properties with regard to neurite regeneration, axonal outgrowth, and repair of damaged synapses in mice [86][87][88][89]. The synthesis of withanolide A has been presented with various synthetic problems. In 2013, Liffert et al. [90] reported a new method for the synthesis of withanolide A by using the Corey-Seebach reaction in one of their key steps. For this purpose, the pregnenolone 94 was protected with TBS, Scheme 13. Synthesis of tetraphenylcyclopentadienones 89a-e.

Scleropentaside A
Scleropentasides are a prime class of natural products that have been extracted from the twigs, leaves, and stems of dendrotrophe frutescens and scleropyrum pentadrum [82], respectively. Both plants exhibit a variety of uses in traditional Asian medicine, including skin treatments, rheumatic pain relief, etc. This innovative class of natural compounds has an unrivaled anomeric-β-glycosidic motif and a furan ring [83]. One of the most iconic members of this class is scleropentaside A, which displays a radical scavenging activity. Boehlich et al. [84] reported an exclusive and general method for the preparation of acylglycosides by utilizing the Corey-Seebach reaction. This methodology has been exclusively used for the short synthesis of scleropentaside A. For this purpose, a silane-protected carbohydrate 90 was reacted with furfural dithiane 91 to obtain product 92, which upon deprotection, afforded sceropentaside A 93 with a good yield (Scheme 14).

Scleropentaside A
Scleropentasides are a prime class of natural products that have been extracted fro the twigs, leaves, and stems of dendrotrophe frutescens and scleropyrum pentadrum [82], spectively. Both plants exhibit a variety of uses in traditional Asian medicine, includi skin treatments, rheumatic pain relief, etc. This innovative class of natural compounds h an unrivaled anomeric-β-glycosidic motif and a furan ring [83]. One of the most ico members of this class is scleropentaside A, which displays a radical scavenging activi Boehlich et al. [84] reported an exclusive and general method for the preparation of ac glycosides by utilizing the Corey-Seebach reaction. This methodology has been exc sively used for the short synthesis of scleropentaside A. For this purpose, a silane-p tected carbohydrate 90 was reacted with furfural dithiane 91 to obtain product 92, wh upon deprotection, afforded sceropentaside A 93 with a good yield (Scheme 14).

Withanolide A
One of the most potent components in the methanolic extracts of ashwagandha is wi anolide A, which was isolated from the roots of Withania somnifera [85]. It has been show to have strong pharmacological properties with regard to neurite regeneration, axo outgrowth, and repair of damaged synapses in mice [86][87][88][89]. The synthesis of withanoli A has been presented with various synthetic problems. In 2013, Liffert et al. [90] report a new method for the synthesis of withanolide A by using the Corey-Seebach reaction 2.9. Steroids 2.9.1. Withanolide A One of the most potent components in the methanolic extracts of ashwagandha is withanolide A, which was isolated from the roots of Withania somnifera [85]. It has been shown to have strong pharmacological properties with regard to neurite regeneration, axonal outgrowth, and repair of damaged synapses in mice [86][87][88][89]. The synthesis of withanolide A has been presented with various synthetic problems. In 2013, Liffert et al. [90] reported a new method for the synthesis of withanolide A by using the Corey-Seebach reaction in one of their key steps. For this purpose, the pregnenolone 94 was protected with TBS, followed by lithiation with dithiane to obtain 95 by using the Corey-Seebach reaction. In the next step, the deprotection of dithiane was achieved by using (N-Chlorosuccinimide) NCS in the presence of dichloromethane (DCM) followed by MOM protection of the OH group to afford aldehyde 96. Aldehyde 96 was treated with vinylogous enolate and LiHMDS in the presence of DMPU and THF, which resulted in the synthesis of unsaturated lactone 97 with an 87% yield and excellent stereoselectivity (dr 93:7). After a few steps, unsaturated enone 98 was formed, which upon treatment with H 2 O 2 (Triton B), hydrazine, and PDC afforded withanolide A 99 in a 30% yield (Scheme 15).

Cholanic Acid Derivatives
Cholanic acid is one of the important intermediates for many reactions. It was extracted from a sea pen by Djerassi et al. [91,92]. In 2007, Shingate et al. [93] reported the stereoselective method for the synthesis of 20-epi cholanic acid derivatives from dehydropregnenolone acetate by using the Corey-Seebach reaction in one of their key steps. The synthesis of cholanic acid was initiated from the chemo-selective catalytic hydrogenation of 16-dehydropregnenolone acetate 100, followed by hydrolysis to obtain compound 101. After a few steps, compound 102 was formed, which was further reacted with 1,3-dithiane using the Corey-Seebach reaction to afford compound 103 and side product 104 with a 77% and 4% yield, respectively. In the next step, compound 103 was treated with SOCl2 Scheme 15. Synthesis of withanolide A 99.

Cholanic Acid Derivatives
Cholanic acid is one of the important intermediates for many reactions. It was extracted from a sea pen by Djerassi et al. [91,92]. In 2007, Shingate et al. [93] reported the stereoselective method for the synthesis of 20-epi cholanic acid derivatives from dehydropregnenolone acetate by using the Corey-Seebach reaction in one of their key steps. The synthesis of cholanic acid was initiated from the chemo-selective catalytic hydrogenation of 16-dehydropregnenolone acetate 100, followed by hydrolysis to obtain compound 101.
After a few steps, compound 102 was formed, which was further reacted with 1,3-dithiane using the Corey-Seebach reaction to afford compound 103 and side product 104 with a 77% and 4% yield, respectively. In the next step, compound 103 was treated with SOCl 2 and pyridine in the presence of DCM to obtain ketene 105 with an 84% yield, which provided iso-methyl ether 106 after a few steps. In the last step, the deprotection of compound 106 was carried out to afford 20-epi cholanic acid derivative 107 (Scheme 16).

Rodocaine
Rodocaine is an important chemical that is used in ophthalmic anesthesia  There are a number of methods that have been developed for the synthesis of this mo cule. In 2017, Meyer et al. [97] developed a new method for the enantioselective synthe of rodocaine through enantioselective hydroazidation by utilizing the Corey-Seebach action in one of their key steps. For this purpose, compound 108 was converted into clopentene 109 through Malaprade glycol, thioacetalization, and the Corey-Seebach re tion, respectively. Compound 109 was then subjected to enantioselective hydroazidat in the presence of (-)-IpcBH2 to afford trans azide 110 with a 61% yield (er 75:25), follow by desulfurization and Boc protection to furnish compound 111. In the last step, co pound 111 was alkylated with iodide 112 to afford the impure rodocaine with a 68% yi (er 74:26), which was precipitated with H2O/MeOH to obtain pure enantiomeric rodoca 113 with a 15% yield (Scheme 17).

Rodocaine
Rodocaine is an important chemical that is used in ophthalmic anesthesia [94][95][96]. There are a number of methods that have been developed for the synthesis of this molecule. In 2017, Meyer et al. [97] developed a new method for the enantioselective synthesis of rodocaine through enantioselective hydroazidation by utilizing the Corey-Seebach reaction in one of their key steps. For this purpose, compound 108 was converted into cyclopentene 109 through Malaprade glycol, thioacetalization, and the Corey-Seebach reaction, respectively. Compound 109 was then subjected to enantioselective hydroazidation in the presence of (-)-IpcBH 2 to afford trans azide 110 with a 61% yield (er 75:25), followed by desulfurization and Boc protection to furnish compound 111. In the last step, compound 111 was alkylated with iodide 112 to afford the impure rodocaine with a 68% yield (er 74:26), which was precipitated with H 2 O/MeOH to obtain pure enantiomeric rodocaine 113 with a 15% yield (Scheme 17).

D-Glucosamine Trimethylene Derivatives
The extension of the carbohydrate chain by using the Corey-Seebach method (dithiane chemistry) is well known [98]. A number of D-glucosamine-based trimethylene derivatives have been synthesized, but these approaches have some limitations regarding the tolerance of leaving groups. In 2006, Chen et al. [99] utilized trimethylene acyl-D-glucosamine to synthesize α-imidate dithiane. To achieve this, compound 114 was treated with n-BuLi to produce stabilized imidate-carba dianion 115, followed by the addition of D 2 O to afford compound 116. The iodination of compound 114 was also performed to check the reactivity, and two different products, 117 and 118, were obtained in different conditions. The carbon atom extended carbohydrate 119 was formed by the reaction of compound 114 with n-BuLi, followed by the reaction with DMF, ethyl chloroformate, and methyl chloroformate. Compound 114 was also treated with cyclohexanone or cyclopentanone to yield compounds 120 and 121. In addition to this, compound 114 was also reacted with substituted D-ribofuranose-3-ulose 122 to afford compound 123 with an average yield (up-to 28%) (Scheme 18).

(−)-Calystegine B 3
As effective and selective glycosidase inhibitors, carbasugars and azasugars are among the most appealing compounds in the world of N-carbohydrates [100]. The majority of the compounds contain five-or six-membered fused-ring structures. Most of them are employed as chemotherapeutic agents to treat viral infections and diabetes. The calystegine compounds belong to the Solanaceae family [101,102], and their analogs have been created since they are thought to be pioneer compounds for novel bioactive drugs. Chen et al.

D-Glucosamine Trimethylene Derivatives
The extension of the carbohydrate chain by using the Corey-Seebach method (dithiane chemistry) is well known [98]. A number of D-glucosamine-based trimethylene derivatives have been synthesized, but these approaches have some limitations regarding the tolerance of leaving groups. In 2006, Chen et al. [99] utilized trimethylene acyl-D-glucosamine to synthesize α-imidate dithiane. To achieve this, compound 114 was treated

Substituted Pyridines
The nitrogen-containing aromatic heterocycles are essential components in pharmaceutical and natural products [105]. Substituted pyridines are extremely evident among them. For three decades, the synthesis of pyridine has gained a lot of attention of from the scientific community [106]. Despite the fact that there are numerous chemical ways to generate such heteroaromatics, there is still a great deal of interest in finding new approaches that would provide quick and precise exposure [107]. Chen et al. [108] developed an efficient method for the synthesis of substituted pyridines by utilizing the Corey-Seebach reaction. The methodology involved the reaction of dithiane 133 with α,β-unsaturated ketones or aldehydes 134 to obtain a series of trisubstituted alkenes 135 in good to Scheme 19. Synthesis of (−)-calystegine B 3 132 by utilizing Corey-Seebach reaction.

Substituted Pyridines
The nitrogen-containing aromatic heterocycles are essential components in pharmaceutical and natural products [105]. Substituted pyridines are extremely evident among them. For three decades, the synthesis of pyridine has gained a lot of attention of from the scientific community [106]. Despite the fact that there are numerous chemical ways to generate such heteroaromatics, there is still a great deal of interest in finding new approaches that would provide quick and precise exposure [107]. Chen et al. [108] developed an efficient method for the synthesis of substituted pyridines by utilizing the Corey-Seebach reaction. The methodology involved the reaction of dithiane 133 with α,β-unsaturated ketones or aldehydes 134 to obtain a series of trisubstituted alkenes 135 in good to excellent yields (62% minimum and 96% maximum). These trisubstituted alkenes 135 underwent Ti-mediated coupling with substituted aldehydes 136 to furnish substituted pyridines 137 with average to good yields (33-82%) (Scheme 20). The role of alkene geometry in this reaction was also explored, and it was observed that the geometry of alkenes did not play any crucial role in the synthesis of pyridines. excellent yields (62% minimum and 96% maximum). These trisubstituted alkenes 135 underwent Ti-mediated coupling with substituted aldehydes 136 to furnish substituted pyridines 137 with average to good yields (33-82%) (Scheme 20). The role of alkene geometry in this reaction was also explored, and it was observed that the geometry of alkenes did not play any crucial role in the synthesis of pyridines. Scheme 20. Synthesis of substituted pyridines 137.

Conclusions
This review article provides a thorough analysis of the synthesis of natural and synthetic compounds which involve the Corey-Seebach reaction as a major step in their synthetic methodologies. The Corey-Seebach reagent is of particular importance in organic synthesis owing to its ability to generate valuable chemical derivatives from basic, easily accessible starting materials. We, therefore, come to the conclusion that Corey-Seebach reagent serves as a synthetic equivalent as well as a protective group for the carbonyl functionality and has extensively been employed in the synthesis of natural products such as lycoplanine A, bisnorditerpene, totarol, ambruticin J, biakamides, as well as synthetic molecules (Bisacyldigermanes, photoinitiators, benzoin-derived diol linkers, substituted pyridines). With the fact that the Corey-Seebach reaction has been the subject of extensive investigation, we anticipate that this analysis will spur synthetic scientists to develop fresh approaches and innovative theories in this area.

Conclusions
This review article provides a thorough analysis of the synthesis of natural and synthetic compounds which involve the Corey-Seebach reaction as a major step in their synthetic methodologies. The Corey-Seebach reagent is of particular importance in organic synthesis owing to its ability to generate valuable chemical derivatives from basic, easily accessible starting materials. We, therefore, come to the conclusion that Corey-Seebach reagent serves as a synthetic equivalent as well as a protective group for the carbonyl functionality and has extensively been employed in the synthesis of natural products such as lycoplanine A, bisnorditerpene, totarol, ambruticin J, biakamides, as well as synthetic molecules (Bisacyldigermanes, photoinitiators, benzoin-derived diol linkers, substituted pyridines). With the fact that the Corey-Seebach reaction has been the subject of extensive investigation, we anticipate that this analysis will spur synthetic scientists to develop fresh approaches and innovative theories in this area.