1． Introduction

Stereoselective construction of all─ carbon quaternary ste-reocenters remains a challenge in organic synthesis, 1 and dur-ing our research on the total synthesis of natural products, we have frequently found dif�culty in constructing a quaternary stereocenter with the desired con�guration. As synthetic tar-gets, we have been interested in bioactive natural products having a prenylated quaternary stereocenter, such as (+)─ gut-tiferone A (1), 2 (-)─ hyphenrone A (2), 3 (+)─ vibsanin A (3), 4 and (-)─ callophycoic acid A (4) 5 (Figure 1). To synthesize such compounds ef�ciently, we embarked on the development of a practical method for achieving this dif�cult transformation.

As a strong candidate approach to this challenge, we thought of using 3,3─ disubstituted allylmetal reagents. Although extensive research has focused on developing stereo-

selective carbonyl allylation reactions, 6 the synthesis of organic compounds containing quaternary stereocenters through the addition of allylmetals to aldehydes is still a challenge. 7

Based on this idea, we have developed two methods for stereoselective synthesis of homoallylic alcohols containing all─ carbon quaternary stereocenters using such carbonyl allylation reactions, and applied these methods to synthetic studies of natural products. In this account, we describe our development of the zinc─ mediated Barbier─ type allylation 8 and allylboration 9 of a sugar─ derived aldehyde, and the syn-theses of (+)─ vibsanin A (3) 10 and the tricyclic skeleton of (-)─ callophycoic acid A (4). 11

2． Construction of All─ Carbon Quaternary Stereocenters by Zinc─ Mediated Barbier─ Type Allylation

The majority of nucleophilic addition reactions using organometallic reagents involve lithium and magnesium. These reactions require the strict exclusion of moisture. Some classes of the Barbier─ type allylation, however, do not require rigor-ously anhydrous reaction conditions, and can be performed effectively in aqueous media. 12 Zinc is the most popular metal for this type of reaction because it is easy to handle and stable in air. To develop a practical method for constructing an all─ carbon quaternary stereocenter, we examined zinc─ mediated Barbier─ type allylation of chiral aldehydes in aqueous media.

As an easily available chiral aldehyde, we used 2,3─ O ─ iso-propylidene─ D─ glyceraldehyde (5) 13 (Table 1). The reaction of 5 with geranyl chloride 6 proceeded in the presence of zinc powder in a mixture of aqueous NH 4Cl─ THF, producing γ ─ adducts which were separated into (3R)─ isomers 8─ A/8─ B (4R/4S＝1:4) and (3S)─ isomers 8─ C/8─ D (4R/4S＝5:1), in yields of 6% and 77%, respectively (entry 1). By using neryl chloride 7 instead of 6, (3S,4S)─ isomer 8─ D with the opposite con�guration of the quaternary stereocenter (4─ position) was preferentially obtained, though a decrease in stereoselectivity was observed (entry 2).

The stereochemical outcome obtained in the allylation of 5 with 6 can be explained using the transition state model depicted in Scheme 1. The allylation is thought to proceed through a 6─ membered, chair─ like transition state. In addi-

Figure 1.　 Natural products having a prenylated quaternary stereocenter.

The Stereoselective Construction of All─ Carbon Quaternary Stereocenters by Allylations and Its Application to Synthetic Studies of Natural Products

Akihiro Sakama 1, Akihiro Ogura 1, Keisuke Yoshida 2, and Ken─ ichi Takao 1＊

1＊Department of Applied Chemistry, Keio University Hiyoshi, Kohoku─ ku, Yokohama 223─ 8522, Japan

2Faculty of Pharmacy, Meijo University 150 Yagotoyama, Tempaku─ ku, Nagoya 468─ 8503, Japan

(Received June 23, 2020; E─ mail: takao@applc.keio.ac.jp)

Abstract: The synthesis of organic compounds containing all─ carbon quaternary stereocenters through the addition of allylmetals to aldehydes is still a challenge. In this account we describe two methods to achieve this transformation stereoselectively: one involves the zinc─ mediated Barbier─ type allylation and the other allylbo-ration of a sugar─ derived aldehyde. These methods were applied to the total synthesis of (+)─ vibsanin A, and the synthesis of the tricyclic core of (-)─ callophycoic acid A.

Vol.78 No.11 2020 （ 41 ） 1039

tion, organozinc reagents have a tendency to form a chelate complex involving the carbonyl and the β ─ alkoxy group. Therefore, the reaction of 5 with 6 preferentially produces 8─ C in accordance with this β ─ chelation/6─ membered model.

This reaction can be performed without using completely anhydrous conditions, providing a practical and operationally simple method for constructing quaternary stereocenters. 8 We then turned our attention to the total synthesis of (+)─ vibsanin A (3) using this Babier─ type allylation.

3． Total Synthesis of (+)─ Vibsanin A

(+)─ Vibsanin A (3) was isolated as the �rst vibsane─ type diterpene by Kawazu from the leaves of Viburnum awabuki, which was previously used in Japan as a �sh poison for �sh-ing. 4 So far, more than 80 vibsane─ type diterpenes have been found, which can be divided into 11─ membered ring, 7─ mem-bered ring, and rearranged classes. They have attracted the attention of many research groups, and the total syntheses of 7─ membered ring and rearranged vibsanes had previously been reported. However, the total synthesis of 11─ membered ring vibsanes had not been achieved. Compound 3 is a syn-thetically challenging target due to its highly functionalized

11─ membered ring skeleton containing an all─ carbon quater-nary stereocenter. When planning the total synthesis of 3, we performed the retrosynthetic analysis shown in Scheme 2. The combination of an intramolecular Nozaki─ Hiyama─ Takai─ Kishi (NHTK) reaction 14 and an allylic rearrangement was expected to assemble the 11─ membered ring skeleton. Sub-strate 9 for the NHTK reaction was divided into upper frag-ment 10 and lower fragment 11, both containing an alkenyl iodide moiety. We envisaged that upper fragment 10 would arise from commercially available 4─ pentynyl acetate 12 through an asymmetric epoxidation, whereas lower fragment 11 would be derived from geranyl chloride 6 using our method involving a Barbier─ type allylation.

The prenylated quaternary stereocenter in lower fragment 11 was formed by the zinc─ mediated Barbier─ type allylation of L─ glyceraldehyde derivative ent ─ 5 15 with 6 (Scheme 3). The reaction generated a 6:1 mixture of diastereomers favoring desired (4S)─ isomer ent ─ 8─ C. Benzylation of ent ─ 8─ C fol-lowed by hydroboration/oxidation provided diol 13. The minor (4R)─ isomer was removed at this stage. The primary alcohol in 13 was selectively silylated, and treating the resultant seco-ndary alcohol with Martin sulfurane regenerated the trisubsti-tuted ole�n to furnish 14 as a single isomer. Deprotection of 14 and subsequent oxidative cleavage of triol 15 provided alde-hyde 16, which was subjected to the Takai─ Utimoto ole�nation to provide lower fragment 11 with high E selectivity.

Upper fragment 10 was prepared from iodo ole�n─ alcohol 17 (Scheme 4), which was obtained from 4─ pentynyl acetate 12 using two known steps. 16 Oxidation of 17 followed by ole�na-tion using Ando reagent 18 17 provided unsaturated ester 19 with good Z ─ selectivity. Ester 19 was reduced with DIBAL─ H to allylic alcohol 20, and then the Sharpless asymmetric epoxi-dation of 20 under stoichiometric conditions generated epo-xide 21 in 80% ee. Finally, oxidation of 21 to the corresponding aldehyde afforded upper fragment 10 in an enantioenriched form.

The next stage was coupling of the upper and lower frag-ments (Scheme 5). Alkenyl iodide 11 was converted into the alkenyllithium intermediate, and then aldehyde 10 was added

Scheme 1.　 Plausible transition state for the Barbier─ type allylation of 5 with 6.

Scheme 2.　Retrosynthetic analysis of (+)─ vibsanin A (3).

Table 1.　Barbier─ type allylation of D─ glyceraldehyde derivative 5.

（ 42 ） J. Synth. Org. Chem., Jpn.1040

to produce the coupling products 22─ A and 22─ B. Because the newly formed stereogenic center (C7) in major product 22─ A had the opposite con�guration to the target, 22─ A was acyla-ted with 3,3─ dimethylacrylic acid under Mitsunobu conditions. The reaction proceeded smoothly, giving ester 23 with con�gu-rational inversion. In addition, the minor product 22─ B was converted into 23 by condensation with stereoretention. Deprotection of 23 followed by oxidation furnished alkenyl iodide─ aldehyde 9. To our delight, the intramolecular NHTK reaction of 9 effected formation of the 11─ membered ring, and

Scheme 3.　Synthesis of lower fragment 11. Scheme 4.　Synthesis of upper fragment 10.

Scheme 5.　Completion of the total synthesis of (+)─ vibsanin A (3).

Vol.78 No.11 2020 （ 43 ） 1041

provided 24 stereoselectively. At this stage, the diastereomer derived from the minor enantiomer of 10 was separated by column chromatography, allowing the isolation of diastereo-merically pure 24. The allylic rearrangement of 24 to 25 was achieved using the Mitsunobu reaction, forming the ole�n with the desired con�guration. Thus, we constructed the functional-ized 11─ membered ring skeleton by combining the intramole-cular NHTK reaction and the Mitsunobu reaction. Chemose-lective methanolysis of diester 25 �nally afforded (+)─ vibsanin A (3). This work was the �rst successful synthesis of a natural 11─ membered vibsane─ type diterpene, and unambiguously established the absolute structure of natural (+)─ vibsanin A. 10

After our total synthesis, (+)─ vibsanin A (3) was found to induce differentiation of myeloid leukemia cells by activating protein kinase C (PKC). 18 We synthesized several vibsanin A analogues, and found new compounds activating PKC and showing anti─ proliferative activity against human cancer cell lines. 19

4． Construction of All─ Carbon Quaternary Stereocenters by Allylboration

In our total synthesis of (+)─ vibsanin A (3), we created an (S)─ con�gured quaternary stereocenter by using ent ─ 5, which was prepared from L─ ascorbic acid in �ve steps. 15 Compound 5 (prepared from D─ mannitol in only two steps) 13 is a more read-ily available starting material, and to enable its use in the syn-thesis of 3, we aimed to develop a method stereochemically complementary to the zinc─ mediated Barbier─ type allylation. We focused on the allylboration reaction, in which chelation with the aldehyde would not be possible because of the limited coordination shell of boron. 20

The allylboration of 5 with geranylboronate 26 21 provided 8─ C/8─ D as a 4R/4S＝1:5 mixture (Table 2, entry 1). Contrary

to the Barbier─ type allylation, (4S)─ isomer 8─ D was obtained as the major product. When 27 was used instead of 26, the reaction preferentially produced (4R)─ isomer 8─ C (entry 2). The stereoselectivity was slightly lower than in the reaction with 26, but was still good.

In both cases (entries 1 and 2), the stereochemical out-comes regarding the quaternary stereocenter were the opposite of those seen for the Barbier─ type allylation using the corre-sponding allyl chlorides. Our proposed transition state for the reaction of aldehyde 5 with boronate 26 is shown in Scheme 6. The allylboration of carbonyl compounds is thought to pro-ceed via a 6─ membered chair─ like transition state providing γ ─ adducts exclusively. In the reaction of 5 with 26, the Felkin─ Anh transition state, which results in the formation of γ ─ adduct 8─ D, is plausible based on the stereoelectronic effect, although steric destabilization by the syn ─ pentane interaction occurs. The other isomers are presumably generated through unfavorable transition states, in which stronger steric interac-tions exist. Thus, a method for stereoselective construction of all─ carbon quaternary stereocenters by allylboration was deve-loped. 9

We have demonstrated the utility of this allylboration by using the major product 8─ D as a chiral building block in a synthesis of lower fragment 11 from our synthesis of (+)─ vib-sanin A (3). 9 The synthetic route is similar to that in Scheme 3, and is not shown on account of limited space.

In our �rst report, we used pinacol ester 26 for the allylbo-ration. To improve the diastereoselectivity, we explored other glycol esters such as neopentyl glycol ester 28 and hexylene glycol ester 29, which were prepared from geraniol and the cor-responding commercially available diborons by palladium─ catalyzed direct borylation (Table 3). 21 The reaction of 5 with 28 provided γ ─ adducts 8─ A/8─ B (A/B＝14:1) in 12% yield and 8─ C/8─ D (C/D＝1:10) in 71% yield, respectively (entry 2). Allylboration with hexylene glycol ester 29 proceeded with slightly higher stereoselectivity, albeit in slightly lower yield (entry 3). To summarize, using these new allylboronate reagents greatly improved the diastereoselectivity to realize a more stereoselective construction of the all─ carbon quaternary stereocenter in (3S,4S)─ isomer 8─ D. 11 We applied this improved method to the synthetic study of (-)─ callophycoic acid A (4).

5． Synthesis of the Tricyclic Skeleton of (-)─ Callophycoic Acid A

(-)─ Callophycoic acid A (4) was isolated by Kubanek and co─ workers in 2007 from the extracts of the Fijian red seaweed Callophycus serratus, and exhibited antibacterial activity

Scheme 6.　 Plausible transition state for the allylboration of 5 with 26.

Table 2.　Allylboration of aldehyde 5.

（ 44 ） J. Synth. Org. Chem., Jpn.1042

against vancomycin─ resistant Enterococcus faecium, as well as antimalarial activity and cytotoxicity against human cancer cell lines. 5 The structure of 4 is characterized by a brominated tricyclic skeleton containing three contiguous stereogenic cen-ters, one of which is an all─ carbon quaternary stereocenter. Compound 4 and its congeners are the �rst diterpene─ benzoic acid hybrids found in macroalgae. Yet, despite the interesting structure and biological activities of 4, no synthetic study had been reported. Focusing on the quaternary stereocenter, we aimed at stereocontrolled synthesis of the tricyclic core of 4 through allylboration. Our retrosynthetic analysis of 4 is shown in Scheme 7. We set tricycle 30 as an advanced interme-diate that can be converted into 4 via bromination with stereo-chemical inversion and extension of the side chain. The tetra-hydrooxepin ring in 30 would be formed by S N2́─ type cyclization of phenol 31, and then the cyclohexane ring in 31 would be constructed by radical cyclization. The substrate for radical cyclization, enyne 32, would be accessible from homo-allylic alcohol 33. We planned to construct the quaternary ste-reocenter in 33 by allylboration of D─ glyceraldehyde derivative 5 using allylboronate 34.

Extensive examinations using a variety of allylboronates proved neopentyl glycol ester 36, prepared from known diol 35, 22 to be a suitable substrate for this synthesis (Scheme 8). Allylboration of 5 with 36 produced a similar stereochemical outcome to the reaction using geranylboronates. The crude reaction mixture was subjected to selective silylation. TBDPS ether 37 (4S/4R＝17:1) was obtained in 51% over three steps with high diastereoselectivity. The secondary hydroxy group of 37 was protected as a TBS ether, and then bis(silyl ether) 38 was subjected to ozonolysis. Subsequent Horner─ Wadsworth─

Emmons ole�nation with phosphonate 39 afforded pure ole�-nated product 40 after removal of the (4R)─ isomer. The termi-nal acetonide of 40 was chemoselectively hydrolyzed using Zn(NO 3) 2·6H 2O. Oxidative cleavage of the resultant diol 41, followed by reduction gave alcohol 42, which was converted into iodide 43. For the next nucleophilic reaction, the ester of 43 was temporarily reduced to an alcohol and protected with a MOM group. Propargylation of MOM ether 44 proceeded smoothly and provided enyne 45 after removal of the TMS group. This compound was reoxidized to methyl ester 46.

With enyne 46 in hand, radical cyclization was performed to construct the cyclohexane ring (Scheme 9a). Reaction with n ─ Bu 3SnH and Et 3B/air followed by acidic protodestanny-lation furnished a mixture of cyclized products 47 and 2─ epi ─ 47 in a 7:1 ratio. We speculate that the cyclization occurred preferentially giving 47 in order to avoid a steric interaction similar to 1,3─ allylic strain between the alkenyl radical and the styryl group (Scheme 9b).

Having achieved the stereoselective formation of the cyclo-hexane ring containing the three contiguous stereocenters, we next focused on forging the tetrahydrooxepin ring. To this end, it was necessary to chemoselectively introduce a leaving group for intramolecular etheration into the allylic methylene (C4). We chose to install a hydroxy group by allylic oxidation. Because changing the phenolic protecting group of 47/2─ epi ─ 47 was required, the allyl group was removed, after which sepa-ration of the 2─ epi ─ isomer from the mixture by column chro-matography provided diastereomerically pure phenol 48 (Scheme 10). This phenol was then acetylated to 49. Repeated treatment of 49 with SeO 2 and TBHP afforded a separable

Table 3.　Allylboration with geranylboronates 28 and 29. Scheme 7.　Retrosynthetic analysis of (-)─ callophycoic acid A (4).

Vol.78 No.11 2020 （ 45 ） 1043

mixture of allylic alcohol 50 and its epimer 51 in reasonable yield.

Our next goal was to construct the tricyclic system of cal-lophycoic acid A via an intramolecular etheration. In Scheme 10, two diastereomeric alcohols 50 and 51 were

obtained. First, mesylation of alcohol 50 was attempted. How-ever, this mesylate tended to form elimination product 53 at ambient temperature (Scheme 11). After investigating the reac-tion conditions, we found that relatively stable allylic chloride 52 was produced via mesylation at 0 ℃ and S N2́ chlorination

Scheme 8.　Synthesis of enyne 46 for radical cyclization.

Scheme 9.　Construction of the cyclohexane ring.

（ 46 ） J. Synth. Org. Chem., Jpn.1044

with LiCl, although formation of the side product 53 could not be avoided. Without separating 52 and 53, the mixture was deacetylated with NaOMe. To our delight, a subsequent intra-molecular S N2 reaction of the generated phenoxide ion pro-ceeded readily to furnish tricyclic ether 54 in 25% yield from 50, but diene 55 was also obtained in 38% yield from 50. Next, we sought to access 54 from epimer 51. Mesylation of 51 fol-lowed by chlorination afforded a mixture of S N2 product 56, S N2́ product 52, and diene 53. The elimination reaction of the intermediate mesylate seemed to be relatively slow because the mesyloxy group is equatorially oriented. Upon treatment with NaOMe, the phenol derived from 56 hardly underwent intra-

molecular S N2́ etheration. Consequently, the mixture of products was treated further with NaH in THF at 40 ℃. Through this sequence, tricycle 54 was synthesized in 65% yield from 51. Compared with the synthesis from 50, tricycle 54 was obtained more ef�ciently, and the formation of diene 55 was suppressed. Therefore, conversion of 50 into 51 was examined. Dess─ Martin oxidation of 50 and subsequent stereoselective 1,2─ reduction with NaBH 4 in the presence of CaCl 2 gave exclusively 51 in good yield. Thus, we had accom-plished the stereoselective construction of the tricyclic skeleton of (-)─ callophycoic acid A (4) from D─ glyceraldehyde deriva-tive 5. 11

In parallel with this strategy, we investigated another approach to the tricyclic core. This synthesis began with the allylboration of D─ xylose derivative 57 23 with hexylene glycol ester 29 (Scheme 12). The reaction showed high stereo-selectivity (dr＝84:13:3), and afforded an inseparable mixture of the γ ─ adducts favoring (5S,6S)─ isomer 58. The palladium─ catalyzed reductive enyne cyclization 24 of 59 proceeded smoothly to provide the desired product 60 as a single diaste-reomer in 98% yield. Treating mesylate 61 with Pd(PPh 3) 4 con-structed the tetrahydrooxepin ring to furnish tricyclic com-pound 62 in a single step. Accordingly, we had achieved another stereocontrolled synthesis of the tricyclic skeleton of (-)─ callophycoic acid A (4), this time from D─ xylose derivative 57. 11

6． Conclusion

To challenge the dif�culties of stereoselective, all─ carbon quaternary stereocenter construction, we have developed two methods: one involves the zinc─ mediated Barbier─ type allylation, and the other allylboration. These reactions are ste-reochemically complementary to each other, and feature prac-tical and convenient conditions. We have applied the reactions to the �rst total synthesis of (+)─ vibsanin A (3), and the stereoselective synthesis of the tricyclic core of (-)─ callophy-coic acid A (4), for which we further created new synthetic strategies. To construct the 11─ membered ring skeleton of 3, an intramolecular NHTK reaction and a Mitsunobu reaction

Scheme 10.　Allylic oxidation on the cyclohexane ring.

Scheme 11.　Synthesis of tricyclic compound 54.

Vol.78 No.11 2020 （ 47 ） 1045

were combined. The radical─ or palladium─ catalyzed reductive cyclization of enynes achieved formation of the functionalized cyclohexane ring of 4 with high stereoselectivity. Our two allylations should be widely applicable to the construction of chiral building blocks bearing quaternary stereocenters. 25 Fur-ther studies, and applications in natural product synthesis are underway in our laboratory.

AcknowledgementsWe thank Professor Kin─ ichi Tadano (Itsuu Laboratory)

for helpful discussions and comments. We gratefully acknowl-edge our co─ workers who participated in these research proj-ects, and their names appear in the reference section. This work was supported in part by the MEXT─ Supported Program for the Strategic Research Foundation at Private Universities, 2012─ 2016, and the Keio University Doctorate Student Grant─ in─ Aid Program.

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Scheme 12.　Another approach to the tricyclic core.

（ 48 ） J. Synth. Org. Chem., Jpn.1046

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PROFILE

Akihiro Sakama was born in Kanagawa, Ja-pan in 1991. He received his Ph.D. in 2020 from Keio University under the direction of Professor Ken─ ichi Takao. Then he joined the Citterio Group at Keio University as a post─ doctoral researcher. His research inter-ests are focused on the stereoselective synthe-sis of structurally complex organic com-pounds, and the development of �uorescent probes.

Akihiro Ogura was born in Tokyo, Japan in 1985. He received his Ph.D. in 2013 from the University of Tokyo under the guidance of Professor Tohru Fukuyama. He moved to RIKEN to conduct post─ doctoral research with Professor Katsunori Tanaka. In 2016 he joined the Takao Group at Keio University as a research associate. His research interests are directed toward the development of novel catalytic reactions, and the total synthesis of structurally interesting natural products.

Keisuke Yoshida was born in Aichi, Japan in 1983. He received his Ph.D. in 2011 from Kyoto University under the direction of Pro-fessor Takeo Kawabata. He conducted post─ doctoral research at Michigan State Univer-sity (Professor Xuefei Huang) for two years, and then from 2013 to 2016, he worked at Keio University (Professor Ken─ ichi Takao) as a research associate. In 2016 he joined the Kawabata group at Kyoto University as a program─ speci�c assistant professor. In 2017 he moved to Meijo University (Professor Shinji Kitagaki), where he is now an assistant professor. His research interests are focused on the development of organic reactions us-ing organocatalysts, and the total synthesis of natural products.

Ken─ ichi Takao was born in Tokyo, Japan in 1967. He received his Ph.D. in 1995 from Keio University under the direction of Pro-fessor Kin─ ichi Tadano. He worked at Saga-mi Chemical Research Center for one year, and then from 1996 to 1998, he was employed at Tokyo University of Science (Professor Susumu Kobayashi) as an instructor. In 1998 he moved to Keio University, where he is now a professor. In the meantime, he has worked with Professor William R. Roush as a visiting researcher at Scripps Florida (2005─ 2006). His research interests are focused on the total synthesis of biologically and structurally in-teresting natural products, and the deve-lopment of stereoselective synthetic organic reactions.

Vol.78 No.11 2020 （ 49 ） 1047