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Total Synthesis of Caprazamycin A: Practical and Scalable Synthesis of syn-#-Hydroxyamino Acids and Introduction of a Fatty Acid Side Chain to 1,4-Diazepanone Hugh Nakamura, Chihiro Tsukano, Takuma Yoshida, Motohiro Yasui, Shinsuke Yokouchi, Yusuke Kobayashi, Masayuki Igarashi, and Yoshiji Takemoto J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b02220 • Publication Date (Web): 08 May 2019 Downloaded from http://pubs.acs.org on May 8, 2019

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Journal of the American Chemical Society

Total Synthesis of Caprazamycin A: Practical and Scalable Synthesis of syn--Hydroxyamino Acids and Introduction of a Fatty Acid Side Chain to 1,4-Diazepanone Hugh Nakamura,† Chihiro Tsukano,*,† Takuma Yoshida,† Motohiro Yasui,† Shinsuke Yokouchi,† Yusuke Kobayashi,† Masayuki Igarashi,‡ and Yoshiji Takemoto*,† †Graduate ‡Institute

School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan

Supporting Information Placeholder ABSTRACT: The first total synthesis of caprazamycin A (1), a representative liponucleoside antibiotic, is described. Diastereoselective aldol reactions of aldehydes 12 and 25–27, derived from uridine, with diethyl isocyanomalonate 13 and phenylcarbamate 21 were investigated using thiourea catalysts 14 or bases to synthesize syn--hydroxyamino acid derivatives. The 1,4-diazepanone core of 1 was constructed using a Mitsunobu reaction, and the fatty acid side chain was introduced using a stepwise sequence based on model studies. Notably, global deprotection was realized under using palladium black and formic acid without hydrogenating the olefin in the uridine unit.

HO

R A (1) Me Me B Me Me C Me

O

R O

Me

O

O

O OMe OMe

MeO

Me

HO

G Me

HO

Me

O

O HO 2C

N Me O H HO

H N

O O

O

HO 2C

OH

HO

O

NH 2 O

H N

O

NMe O

N

O

HN

N Me O H HO

O

OH

Caprazol (2)

O

N

N Me O H HO

HO

H N

O

NMe O

NH 2

O

NMe O

NH 2

HO

Me

O

Caprazamycins Me

D Me E Me Me F

HO

O

N OH

CPZEN-45 (3)

Figure 1. Caprazamycins, caprazol, and CPZEN-45.

Introduction Liponucleoside antibiotics are a class of natural products with structures comprising uridine attached to amino acids, namely 5’-C-glycyluridine, an aminoribose, and a fatty acid side chain. Examples include caprazamycins,(1) (2) (3) liposidomycins, muraymycins, A-90289,(4) and (5) sphaerimicins (Figures 1 and 2). Several liponucleoside antibiotics inhibit bacterial translocase MraY, which is a peptide glycan enzyme.(6) In the biosynthetic pathway, MraY is located upstream of the enzyme targeted by -lactam antibiotics and glycopeptide antibiotics (such as vancomycin). Therefore, novel antibiotics targeting MraY are expected to have a broad antimicrobial activity spectrum, including against multi-drug resistant bacteria such as methicillinresistant Staphylococcus aureus (MRSA) and vancomycinresistant S. aureus (VRSA). Caprazamycins were isolated from Streptomyces sp. MK730-62F2 by Igarashi and coworkers in 2003 (Figure 1).(1) Structurally, these molecules possess a 1,4-diazepanone, which is a seven membered ring containing two nitrogen atoms, retaining the common motif of several liponucleoside antibiotics. The biosynthesis of caprazamycins was proposed through in vivo and in silico analysis of the biosynthetic gene cluster.(7) Recently, an enzyme catalyst that promotes an aldol-type condensation with glycine and uridine-5’aldehyde to construct 5’-C-glycyluridine was identified.(8) Caprazamycins show

HO R A Me

R

Me B C

A4 B5

HO

Me

D2

O O

Me

O

NH 2 O O

NMe O O

O

HO 2C N Me O H Liposidomycins HO (Total synthesis: no report)

Me

OH N

HN

R

Me

O

O O HO 2C

HO H

Me

H N

H N

O

OH

N H NH

O Me

O O OMe

MeO OMe

N

H HO

OH

HO HO

O

NH 2

O O

Me

O

N OSO 3H

OH O

OH

OH O HN

N O

HO

H N

O

NMe O

O

Me Sphaerimicin A (Total synthesis: no report) unknown stereochemistry

O

HO 2C

HO 2C N Me O H A-90289 A HO (Total synthesis: no report)

Me Me Me Me Me

O

O

Muraymycins

NH

O Me

O

H N

O

O O

NH 2

HO

Me H N

O

H N

Me

OH

O

H N

O O O

N

H

HO 3SO

OH

Figure 2. Structures of representative liponucleoside antibiotics.

ACS Paragon Plus Environment

O

N

HO

Me R

N H

Me

H N

O

NH 2 Me

C2

HO 3SO O

O

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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HO Me O

Me

Me

O Me

O

O

O

O OMe OMe

CbzO

Me

Troc O N

tBuO

2C

HO

N

OH TBSO

Bulky reagent

Me 17

O

pNs

BnO 2C

[Intramolecular Mitsunobu reaction]

H

O

O

BOM O N N

Me Me

O

NMe 2

N H

O

CF 3

O HN

(S, S)-Thiourea catalyst O

O

EtO 2C EtO 2C

OEt NCO 13 [Organocatalyzed aldol reaction] EtO

BOM O N

O O

H

O

O

N

O

N

O H O

O

N Thermodynamic control

F

O

N3

14a

BOM N O

O

O

Me Me 8

N N H

O

pNsHN

[Introduction of -hydroxy amino acid]

O

NHCbz

O

6a Me Me

O

12

7a

NHMe

CF 3

O

Et Et

TBSO

O

O 19

HO

N Me O H O

O

[Desymmetrization]

N

S

H

BnOH

O

BOM N O BnO 2C

O

O

HN

OBn

18

Me

OTBS NHCbz

O

5

O

O

O O

CO 2tBu

O

nC12H25

[Asymmetric reduction]

OBn O

Et Et

N

N Me O H OCbz CbzO Protected caprazol

Ph 2 P RuBr 2 P Ph 2

OH OBn

OMe OMe

PPh 3 N

OH

16 MeO

O

N

O

OH

15

BOM O N

O O

O

Me

OH

4

O

O

N Me O H HO Caprazamycin A (1)

H N

O

NMe O

nC12H25

O

NHCbz

CbzO HO

O

O

NH 2

O

HO 2C

O

MeO

BnO 2C

O

O OMe OMe

MeO

Me

HO

O

O

9 Et Et

pNsHN

MeO 2C [Practical synthesis of -hydroxy amino acid]

Me Me 11a

[-Selective Glycosylation]

O

BOM O O N OH HO N O

O

Me Me syn--hydroxy amino acid (10)

Scheme 1. Retrosynthetic analysis of caprazamycin A (1)

antibacterial activity against Mycobacterium tuberculosis, including the multi-drug resistant strain (MDR-TB), by inhibiting MraY as mentioned above.(1) Through caprazamycin derivatization, Takahashi and coworkers developed CPZEN-45, which exhibits more potent antibacterial activity, particularly against extensively drug-resistant tuberculosis (XDR-TB).(9) As MDR-TB and XDR-TB are resistant to at least four of the core anti-TB drugs, including isoniazid and rifampicin, they present a potential public health problem. Therefore, caprazamycins and CPZEN-45 are receiving attention as seed compounds for future effective antibiotic drugs. Owing to its important biological activity and complex structure, we expected a total synthesis of caprazamycins to provide not only a synthetic sample and route for synthetic analogs, but also an opportunity to develop new synthetic strategies. Synthetic plan

When we began investigating the synthesis of liponucleoside antibiotics, the total synthesis of caprazamycins and liposidomycins had yet to be reported, although various synthetic studies towards liponucleoside antibiotics had been published.(10–14) In 2008, Ichikawa, Matsuda, and coworkers achieved the first total synthesis of caprazol (2), which is a core structure in caprazamycins.(6e) In their synthesis, a Sharpless aminohydroxylation and reductive amination were key reactions for constructing the syn--hydroxyamino acid moiety and 1,4-diazepanone core, respectively. After this landmark report, Shibasaki, Watanabe, and coworkers reported a total synthesis of caprazol (2) in 2013 based on a Cu-catalyzed diastereoselective aldol reaction used to construct the syn-hydroxyamino acid moiety.(13c) However, the introduction of a caprazamycin-type fatty acid side chain has not been reported. These preceding studies indicated that the synthesis of liponucleoside antibiotics presented the following challenges:


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(i) Construction of the syn--hydroxyamino acid moiety, (ii) formation of the 1,4-diazepanone core, and (iii) introduction of the fatty acid side chain. To achieve a total synthesis of caprazamycin A (1), fatty acid side chain 4 would need to be introduced to caprazol core 5 at the late stage because these substructures were expected to be unstable under acidic and basic conditions due to the presence of -acyloxyester and acyloxy acetal moieties (Scheme 1). Benzyl (Bn), benzyloxymethyl (BOM), and benzyloxycarbonyl (Cbz) groups were selected as protecting groups for the caprazol core 5 that could be removed under mild conditions. The 1,4diazepanone motif in 5 would be constructed through a Mitsunobu reaction(15) of alcohol 6a, itself accessed from syn-hydroxyamino acid derivative 10 thorough -selective glycosylation with glycosyl fluoride 9(12e) and coupling with secondary amine 7a. To construct the syn--hydroxyamino acid moiety, we developed an asymmetric synthesis of trisubstituted oxazolidinones through the thiourea-catalyzed aldol reaction of 2-isocyanatomalonate diester 13.(16,17) Extending this method, syn--hydroxyamino acid derivative 10, which is a protected 5’-C-glycyluridine, would be synthesized from aldehyde 12 through a diastereoselective aldol reaction with 13 using thiourea catalysts 14, followed by ring opening of the resultant oxazolidinone 11a and decarboxylation. In this aldol reaction, the thiourea catalyst must precisely recognize a nucleophilic site (aldehyde) to achieve high stereoselectivity, which is challenging owing to the presence of several functionalities, including ether, imide, and N,O-acetal groups. The fatty acid side chain would be synthesized by coupling rhamnose derivative 15, β-hydroxyester 16, and carboxylic acid 17 (vide infra). In this report, we describe in full detail the first total synthesis of caprazamycin A, which was achieved by overcoming the three challenges described above.(18) Results and discussion 1. Diastereoselective synthesis of syn--hydroxyamino acid moiety To investigate the diastereoselective aldol reaction, diethyl isocyanomalonate 13 was prepared from diethylaminomalonate hydrochloride 20 using triphosgene following a literature procedure (Scheme 2).(19) As diethyl isocyanomalonate 13 readily polymerizes in the presence of trace amounts of water, it was used immediately after preparation. When water was removed by Kugelrohr distillation, the distilled diethyl isocyanomalonate 13 could be stored for several weeks. Phenyl carbamate 21, which is much more stable than 13, was also prepared in 97% yield by treating 20 with phenyl chloroformate and sodium bicarbonate under Schotten–Baumann conditions.

triphosgene (0.63 eq.) activated charcoal O EtO

O OEt NH 2 •HCl 20

1,4-dioxane (1.4 M) 80 to 100 °C, 59% O Cl (1.5 eq.) PhO NaHCO3 (2.2 eq.) H2O / Et2O = 1:2 (0.2 M) rt, 97% [one step], [practical], [scalable], [bench stable]

O

O OEt

EtO N

C 13 O 2 g prepared O EtO HN

O OEt OPh

21 O 30 g prepared

Scheme 2. Preparation of isocyanate 13 and phenylcarbamate 21.

Initially, the diastereoselectivity of the aldol reaction of aldehyde 12, prepared from a known protected uridine by IBX oxidation,(20) with diethyl isocyanomalonate 13 or phenylcarbamate 21 was examined in the absence of thiourea catalyst 14a (Table 1). While the aldol reaction with isocyanate 13 using 1,8-diazabicyclo(5.4.0)-7-undecene (DBU) as base (10 mol%) afforded oxazolidinones 11a and 11b in 42% yield, no selectivity was observed (entry 1). Using Et3N or K2CO3 as base did not improve the selectivity (entries 2 and 3). Under these conditions, a small amount of byproduct 22 was obtained through the reaction of products 11a and 11b with diethyl isocyanomalonate 13. Therefore, less-reactive phenylcarbamate 21 was employed as a nucleophile. Treatment of aldehyde 12 with phenylcarbamate 21 (1.0 equiv.) and DBU (1.0 equiv.) in THF at room temperature gave a 1:2.2 mixture of desired oxazolidinone 11a and undesired isomer 11b in 59% yield through phenylcarbamate addition and PhOH elimination (entry 4). To control the selectivity through chelation, several additives were tested.(11v,21,22) Adding ZnCl2 did not affect the selectivity (entry 5). The aldol reaction with LiBr (1.0 equiv.) resulted in a 56% yield with a 1:1.5 dr (entry 6). In this reaction, a small amount of 23 was obtained from elimination of the uracil moiety. To reverse this diastereoselectivity, we applied the same conditions using (S,S)-thiourea catalyst 14a, which was developed for the asymmetric aldol reaction of aldehydes.(16) The reaction of 12 with diethyl isocyanomalonate 13 in the presence of 14a (10 mol%) proceeded smoothly, affording desired oxazolidinone 11a as the major product (64%, 3.1:1 dr, entry 7). It was significant that the selectivity of this aldol reaction could be reversed using an organocatalyst. Both the yield and diastereoselectivity were improved (77%, 6.5:1 dr) using (S,S)-thiourea catalyst 14b (10 mol%) bearing a bulky tertiary amine moiety (entry 8). The amount of catalyst 14b could be reduced to 7 mol%, although this slightly decreased the diastereoselectivity. Interestingly, the formation of byproduct 22 was suppressed by reducing the amount of catalyst 14b. When the amount of catalyst was reduced to 5 mol%, the reaction proceeded slowly to give oxazolidines 11a and 11b in 68% yield, but with 4.2:1 dr, and a small amount of starting



Page 4 of 18

Table 1. Diastereoselective aldol reaction of aldehyde 12 with thiourea catalysts 14. CF 3 BOM O N

O O

H

H

O

O

N

S R 2N

N N H H R = Me: (S, S)-14a R = nC5H11: (S, S)-14b

O

Me Me

or CF 3

O EtO

12

Simple base

O HN EtO 2C EtO 2C

O

H

O

O OEt R' 13 or 21 (1.0 equiv.)

BOM O N

O O

HN

N

O

O

BOM O N

O

EtO 2C EtO 2C

O

H

N

O

O

O

Me Me

Me Me

11a (desired)

11b (undesired)

[Organocatalyzed aldol reaction] entry

nucleophile (R')

cat. 14a or 14b or base

solvent

results (11a : 11b)

byproduct

1 2 3

13 (R' =NCO) 13 (R' =NCO) 13 (R' =NCO)

DBU (10 mol%) Et3N (10 mol%) K2CO3 (10 mol%)

PhMe PhMe PhMe

42% (dr = 1:1) 50% (dr = 1:1.8) 60% (dr = 1.3:1)

22: 27% 22: 10% 22: 13%

4 5

21 (R' = NHCO2Ph) 21 (R' = NHCO2Ph)

DBU (100 mol%) DBU (100 mol%), ZnCl2

THF THF

59% (dr = 1: 2.2) 31% (dr = 1:2.1)

 

6

21 (R' = NHCO2Ph)

DBU (100 mol%), LiBr

THF

56% (dr = 1:1.5)

23: 3.8%

7

13 (R' =NCO)

(S,S)-14a (10 mol%)

PhMe

64% (dr = 3.1:1)

8

13 (R' =NCO)

(S,S)-14b (10 mol%)

PhMe

77% (dr = 6.5:1)

22: 7% 22: 9%

9

13 (R' =NCO)

(S,S)-14b (7 mol%)

PhMe

81% (dr = 5.0:1)

22: 0%

10

13 (R' =NCO)

(S,S)-14b (5 mol%)

PhMe

68% (dr = 4.2:1)

a)

11

13 (R' =NCO)

(R,R)-14b (10 mol%)

PhMe

80% (dr > 1:20)

22: 9.5%

EtO 2C EtO 2C

O

O N H

N

EtO 2C

BOM O N

O O

H

O

N

CO 2Et O

O

Me Me

byproduct 22 O

BOM O N

HN

byproduct 23

a) 15% of starting material 12 was recovered.

material 12 was recovered (entry 10). Interestingly, the aldol reaction using (R,R)-thiourea catalyst 14b (10 mol%) gave undesired isomer 11b in 80% yield in a highly diastereoselective manner (>1:20 dr) (entry 11). These results indicated that the aldol reaction of aldehyde 12 with (R,R)thiourea catalyst 14b was a matched pair that afforded undesired isomer 11b. To explain this diastereoselectivity, a computational model study of this thiourea-catalyzed aldol reaction using benzaldehyde was conducted based on a DFT calculation (Scheme 3a, B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level).(23) The calculation suggested that transition state A was more favorable than transition state B, in which there was steric repulsion between the phenyl and isocyanate groups. Transition state C, which is another possible transition state towards undesired isomer 24b, was not more favorable than B, because C would be destabilized by steric repulsion between the tertiary amine and uracil moieties. Consequently, isocyanomalonate 13 would approach from the Si face of benzaldehyde to give Sisomer 24a. Indeed, this reaction gave S-isomer 24a in 87% yield with 88% ee.(16) Considering these results, the stereoselectivity of the reaction of aldehyde 12 with 13 using thiourea catalyst 14 was rationalized using the following reaction mechanism (Scheme 3b). Initially, thiourea catalyst 14 recognizes the two carbonyl groups of isocyanomalonate 13

through hydrogen bonding. The protonated tertiary amine moiety of thiourea catalyst 14 interacts with the carbonyl group of aldehyde 12 through hydrogen bonding to afford transition state D rather than transition state E. Subsequent cyclization of the resultant alcohol with isocyanate gave desired oxazolidinone 11a as the main product. We also investigated the aldol reaction of the related aldehydes 25–27,(24–26) in which two hydroxyl groups were protected as benzyloxymethyl (BOM), triisopropylsilyl (TIPS), and t-butyldimethylsilyl (TBS) ethers instead of isopropylidene acetal (Table 2). When aldehyde 25 was treated with isocyanomalonate 13 and (S,S)-thiourea 14a in toluene at 0 °C to room temperature, the reaction proceeded to give desired product 28a in 55% yield with >9:1 dr (entry 1). In contrast, when (R,R)-thiourea catalyst 14b was used in an attempt to reverse the diastereoselectivity, diastereomer 28b was obtained as a minor product (2:1 dr, entry 2). As such diastereoselectivity was not obtained using aldehyde 12 bearing an isopropylidene acetal, it was assumed that this selectivity was derived from the bulkiness of the hydroxy protecting groups and/or the conformation of aldehyde 25.(27) Therefore, the reaction was also performed without chiral thiourea catalyst. When potassium carbonate was used as a basic catalyst, the reaction proceeded with high diastereoselectivity (entry 3).


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CF3

(a)

S O

F 3C H

N H

O O O

benzaldehyde CF 3

N H

N H

O transition state A (favored, G‡ = 0 kcal/mol) CF3

NMe 2

cat. (10 mol%) 14a O

C

N

F3C

NCO

[Enantioselective aldol reaction]

EtO O

N H

OH O O

O (S)

Ph

S-isomer 24a 88% ee

C

S O N

H

Me

OEt

N

HN EtO 2C EtO 2C

F 3C

N H

O (R)

Me N H

O O O

Ph

EtO H

R-isomer 24b

N+ H

Me

OEt N

steric C repulsion O transition state C (unfavored, G‡ = +4.42 kcal/mol)

from Re face

transition state B (unfavored, G‡ = +1.95 kcal/mol) (b)

HN EtO 2C EtO 2C

Me

N H

13

Me

from Si face

S

OEt

H

CF3

O

EtO

O N+

H OEt

EtO

S F 3C

Me

N H

steric repulsion

CF 3 S BOM O N

O O

H

H

O

O

N

N CF 3 H NR 2 cat. (10 mol%) 14a or 14b (R = Me or nC5H11) O

O

Me Me 12

O

N H

O NCO

H

O OEt

EtO

O

HN EtO 2C EtO 2C

13

O

O

BOM O N

O N

EtO 2C EtO 2C

O

O

N

O

11b Me Me undesired (minor)

Me Me desired (major) 14a (R = Me)

H

O

11a

[Diastereoselective aldol reaction]

O

HN

BOM O N

O

64% (dr = 3.1:1)

14b (R = nC5H11) 77% (dr = 6.5:1)

F 3C

CF3 R R

N+ H

N H

N H

CF3

Si-face attack

N O

C

N+ H

N H

O O

N

O

EtO H

R

BOM O N

O

O OO

S

R

S

EtO

O

O

Me Me

(a) transition state D (favored)

Re-face attack

CF3

OH OEt

N OC

OEt

H

N H

O N

H

O

O O

Me Me

BOMN O (b) transition state E (unfavored)

Scheme 3. (a) Computational study of thiourea-catalyzed aldol reaction using benzaldehyde and catalyst 14a, based on B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) (in a vacuum) using Gaussian 09; (b) rationalization of diastereoselectivity of thiourea-catalyzed aldol reaction of aldehyde 12



Page 6 of 18

Table 2. Diastereoselective aldol reaction of aldehydes 25–27 with diethyl isocyanomalonate 13 and phenylcarbonate 21. CF 3 S BOM O N

O O

H

H

N

O

R'O

R 2N

N H

O HN

(S,S)-14a (R = Me) 14b (R = nC5H11) O

OR'

25 (R' = BOM) 26 (R' = TIPS) 27 (R' = TBS)

or Simple base CF 3

N H

O

EtO R''

PhMe, temperature

nucleophile (R'')

EtO 2C EtO 2C

OR

temperature

results (a:b)

1

25 (R' = BOM)

13 (R'' = NCO)

(S,S)-14a (60 mol%)

0 °C to rt

28: 55% (dr = 9:1)

25 (R' = BOM)

13 (R'' = NCO)

(R,R)-14b (60 mol%)

0 °C to rt

3

25 (R' = BOM)

13 (R'' = NCO)

K2CO3 (60 mol%)

0 °C to rt

28: 46% (dr = 2:1) 28: 68% (dr = 9:1)

4

26 (R' = TIPS)

13 (R'' = NCO)

K2CO3 (10 mol%)

0 °C

5

26 (R' = TIPS)

13 (R'' = NCO)

Et3N (10 mol%)

0 °C

29: 53% (dr = 7:1)

6

26 (R' = TIPS)

13 (R'' = NCO)

DIPEA (10 mol%)

0 °C

29: 71% (dr = 13:1)

7

26 (R' = TIPS)

21 (R'' = NHCO2Ph)

K2CO3 (100 mol%)

0 °C to rt

29: 62% (dr = 13:1)

8

27 (R' = TBS)

21 (R'' = NHCO2Ph)

K2CO3 (100 mol%)

0 °C

30: 84% (dr > 20:1) (17.9 g scale)

Me O O H

O

H

TBSO

C

27 O

transition state F G‡ = 0 kcal/mol (favored)

BOM O N

O N

EtO 2C EtO 2C

OH

N

O

(S)

H

TBSO

OTBS

31a (desired)

Me Si Me tBu from Si face

O

30a

O

OMe

MeO

C

O Si tBu Me

O

OTBS

O Me

O H

O

N

O

H

N

N

BOM O N

O

OR

O N BOM

O

O

N

29: 60% (dr = 4.6:1)

O

Me

O

28b (R = BOM) 29b (R = TIPS) 30b (R = TBS) (undesired)

2

O

H

RO

cat. 14a or 14b or base

BOM O N

O O

HN

N

O

28a (R = BOM) [practical] 29a (R = TIPS) [scalable] 30a (R = TBS) [inexpensive] (desired) 17.9 g prepared in one batch

[Diastereoselective aldol reaction] aldehyde (R')

H

RO

13 (R = NCO) or OEt 21 (R = NHCO2Ph) (1.0 equiv.)

entry

O

EtO 2C EtO 2C

O

BOM O N

O

NCO

Me

13

H

O O O

C

O

N BOM O

H

N O

N Me

transition state G G‡ = +2.10 kcal/mol (unfavored)

O

O Me Si Me tBu

O Me

O Si tBu Me

from Re face

O C

BOM O N

O N

EtO 2C EtO 2C

OH

N

O

(R)

H TBSO

OTBS

31b (undesired)

30b

Scheme 4. Computational study of diastereoselective aldol reaction of aldehyde 27 with isocyanate 13, based on B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) (in a vacuum) using Gaussian 09.


Page 7 of 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The reaction of aldehyde 26, bearing TIPS groups, with isocyanomalonate 13 gave desired oxazolidinone 29a as the major product with 4.6:1 dr. The selectivity was improved by using a tertiary amine, with diisopropylethylamine (DIPEA) proving particularly effective (entries 5 and 6). Furthermore, we attempted reacting 26 with phenylcarbamate 21, which was easier to handle than isocyanomalonate 13. Although 1 equiv. of potassium carbonate was required, this reaction proceeded smoothly to give desired oxazolidinone 29a in 62% yield with 13:1 dr (entry 7). These conditions using 21 could be applied to a large-scale synthesis from aldehyde 27 bearing a TBS group (17-g scale), which could be readily prepared from uridine. The desired oxazolidinone 30a was obtained in 84% yield with excellent selectivity (entry 8). To explain this diastereoselectivity, we estimated an activation energy for the reaction of aldehyde 27 with isocyanate 13 using DFT calculation at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level (Scheme 4). (23) The results indicated that the activation energy for transition state F, which affords desired adduct 31a, was 2.10 kcal/mol lower than that of transition state G, which affords undesired adduct 31b. In transition state G, there is steric repulsion between an ester group in 13 and a silyl group in 27, which would make transition state F preferable. Resulting adducts 31a and 31b would immediately cyclize to give oxazolidinones 30a and 30b, respectively. Therefore, desired oxazolidinone 30a would be the major product. Obtained aldol adducts 11a, 28a, and 30a were converted into syn--hydroxyamino acid derivatives 10, 38, and 39 (Scheme 5). Selective monohydrolysis of 11a, 28a, and 30a followed by decarboxylation gave thermodynamically stable trans-oxazolidinones 32–34, respectively. Transesterification of 32–34 using a tetranuclear zinc cluster(28) to afford methyl esters 35–37 was essential for concise oxazolidinone ringopening. O HN EtO 2C EtO 2C

O O O H RO

O BOM O N O 1. KOH or HN N LiOH aq. THF EtO 2C H

OR

11a, 28a, 30a

O

pNsHN

OH O

MeO 2C

H

2. DBU THF 70 °C

BOM O N

O O

N MeOH, 50 °C

Zn4(OCOCF3)6O RO OR [Single diastereomer] 32 (R = CMe2): 86% (2 stpes) 33 (R = BOM): 64% (2 stpes) 34 (R = TBS): 71% (2 stpes)

BOM O N 1. pNsCl N NaH, DMF

O HN

2. NaOMe MeO 2C MeOH

RO OR 10 (R = CMe2): 65% (2 steps) 38 (R = BOM): 77% (2 steps) 39 (R = TBS): 57% (2 steps) [syn--hydroxy--amino acid derivatives]

BOM O N

O O O

N

H RO

OR

35 (R = CMe2): quant. 36 (R = BOM): 91% 37 (R = TBS): quant.

After introducing a p-nitrobenzenesulfonyl (pNs) group, the oxazolidinone ring was opened by treatment with NaOMe to afford syn--hydroxyamino acid derivatives 10, 38, and 39 in good yields. Protected compounds 10, 38 and 39 are useful intermediates for the synthesis of liponucleoside antibiotics. Indeed, we achieved the total synthesis of CPZEN-45 (3) from intermediate 39 in 2016.(14a) 2. Introduction of a fatty acid side chain using model 1,4diazepanone Although Shibasaki, Watanabe, and coworkers had reported a synthesis of the fatty acid side chain of caprazamycin B,(13d) the introduction of fatty acid side chain 4 onto a diazepanone ring had not been reported before we began this synthetic study. Presumably, this was due to the fatty acid side chain containing an unstable -acyloxycarboxylic acid structure, meaning that elimination and acyl group rearrangement might occur under basic conditions (Figure 3). NH 2

[-Elimination] HO Me

O Me MeO

O

O

O

O

O Me O HO C 2 OMe OMe [Epimerization] [Retro-aldol reaction]

HO NMe O

O O

H N

O

O N N H Me O HO OH Caprazamycin A (1)

Figure 3. Predictable side-reactions when introducing the fatty-acid side chain of caprazamycin A (1)

Furthermore, several side reactions on the diazepanone ring, such as epimerization, -elimination, and retro-aldol reactions, were expected. Therefore, we initially planned to establish a synthetic route toward model substrate 40 by introducing fatty acid side chain 4 onto diazepanone 41 (Scheme 6). Simple diazepanone 41 would be synthesized by coupling anti--hydroxy amino acid derivative 7b with carboxylic acid 43, derived from serine,(29) followed by an intramolecular Mitsunobu reaction. To prevent undesired side reactions of the -hydroxy amino acid moiety under Mitsunobu conditions, determining appropriate reaction conditions and protecting groups was important. Fatty acid side chain 4 would be synthesized by coupling known rhamnose derivative 15(30) with carboxylic acid 17, followed by condensation with -hydroxy ester 16 (Scheme 1). Intermediates 16 and 17 would be prepared by the Noyori asymmetric reduction of keto ester 18 and the desymmetrization of 3-methyl glutaric anhydride 19, respectively.(31,32)

Scheme 5. Synthesis of syn--hydroxyamino acid derivatives 10, 38, and 39.



Me

side chain, compounds 41a and 41b were prepared by introducing methyl and 2,2,2-trichloroethoxycarbonyl (Troc) groups, respectively. In the synthesis of 41a, an ,unsaturated ester 50 was obtained as byproduct owing to the basic workup after treatment with aqueous hydrogen fluoride (HF). Consequently, the isolated yield of 41a was low.

O Me MeO

O

O

O

O OMe OMe

Me

O

O

EtO 2C

40

NMe OBn N Me O

OH

O O

Me

O

O

O OMe OMe

MeO

Me

OH

O

4

OH CO 2Et

EtO 2C

[Introduction of the unstable side chain] Me

4 steps OH L-(+)-diethyltartarate (ref. 32a)

HO EtO 2C

NR

OBn O

N Me O 41

[Mitsunobu reaction]

pNsHN

OH 43 BnO pyridine, DCM TBSO Me

OTBS

EtO 2C

pNs HN

TBSO NHMe 7b

OBn

HO O 43

[Amidation]

Page 8 of 18

TBSO EtO 2C

OH pNs HN OBn N Me O

EtO 2C

OH HO

CO 2Et

45 N3 (known)

1. TBSCl, Imid. 1. TBSOTf 2. H2, Pd/C 2,6-lut., 81% 3. pNsCl, DIPEA (for R = Et) 24% (4 steps) 2. MeI, K2CO3 3. PhSH, K CO 2 3 OTBS OH CO 2R 82% (2 steps) TBSO CO 2Et 7b (R = Et) 7a (R = Bn)

NMe 2

BH3·SMe2 NaBH4 THF (ref. 32b)

44 N3 (known)

NHMe

Cl

Me

CO 2Et

57%

or (for R = Bn) NH pNs 2. Zn4(OCOCF3)6O (cat.) 46 PhMe/BnOH, heat, 64% 3. MeI, K2CO3 4. PhSH, K2CO3 60% (2 steps)

42

(R' = TBS, PMB)

OR TBSO

Scheme 6. Planned synthetic route for model diazepanone 41 bearing a fatty acid side chain.

The synthesis started with known diol 45, prepared from L(+)-diethyltartrate in a five-step transformation (Scheme 7).(33) Selective silylation of the primary alcohol followed by azide reduction gave an amine that was then protected as the corresponding pNs-amide. Resultant alcohol 46 was converted to anti--hydroxyamino acid derivative 7b through silylation of the secondary alcohol, introduction of a methyl group, and removal of the pNs group. Compound 7b was coupled with carboxylic acid 43, derived from L-serine,(14c,29) using Ghosez’s reagent(34) to afford compound 47 in 57% yield. After selective removal of the TBS group by treatment with 10camphorsulfonic acid (CSA) in MeOH–CH2Cl2 (2:3), the Mitsunobu reaction(15) of obtained alcohol 42 using diethyl azodicarboxylate (DEAD) and PPh3 proceeded smoothly to give 1,4-diazepanone 48 in 92% yield. Previous studies reported that both the hydroxy group and ester on the 1,4-diazepanone ring were oriented in pseudo-axial positions.(11u,v,y) In contrast, our DFT calculation suggested that the siloxy group and ester on 1,4-diazepanone 48 were oriented in pseudo-equatorial and pseudo-axial positions, respectively (Figure 4, conformation X). Conformation X was more stable than conformation Y, in which both substituents were oriented in pseudo-axial positions, presumably owing to the presence of a bulky substituent (pNs group) on the nitrogen atom. The coupling constant of 3.3 Hz observed between Ha and Hb did not contradict predicted conformation X. Compound 48 was converted to secondary amine 49 in 90% yield by treatment with PhSH and K2CO3. As a model study for introducing the

HN

EtO 2C

PPh3 H DEAD TBSO b OBn PhMe

pNs

N Ha Me O [Mitsunobu (JHa,Hb = 3.3 Hz) reaction] 48 47 (R = TBS)

DMF EtO C 2 90%

42 (R = H)

NMe OBn EtO 2C

OBn PhSH K2CO3 TBSO

84% EtO 2C

N Me O

CSA MeOH 68%

pNs N

HO EtO 2C

N Me O 50

14% (undesired)

NR OBn N Me O

41a (R = Me) 41b (R = Troc)

NH OBn N Me O 49

(for R = Me) 1. (CH2O)n NaBH(OAc)3 AcOH, 93% 2. 48% aq. HF CH3CN, rt, 66% or (for R = Troc) 1. TrocCl, pyridine 2. 48% aq. HF 99% (2 steps)

Scheme 7. Synthesis of 1,4-diazepane 41 using a Mitsunobu reaction.

TBSO

Hb

pNs N

OBn

EtO 2C

N O Ha Me 48 (JHa,Hb = 3.3 Hz)

X G = 2.55 kcal/mol

Y G = 0 kcal/mol

Figure 4. Possible conformations X and Y of compound 48, calculated using Gaussian ‘09 at the B3LYP/6-31G(d) level of theory (DFT).


Page 9 of 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Next, the synthesis of a fatty acid side chain 4 started with the desymmetrization of 3-methyl glutaric acid anhydride 19 using a cinchona alkaloid catalyst developed by Song and coworkers (Scheme 8).(32) The resulting carboxylic acid 17 (92% ee) was coupled with L-rhamnose derivative 15(30) through acid chloride formation to give ester 51. After separating a small amount of the undesired diastereomers, a benzyl group was removed by hydrogenolysis in the presence of Pd/C to afford carboxylic acid 52. -Hydroxybenzyl ester 16 was synthesized by Noyori asymmetric reduction(31) of known -ketoester 18,(35) which was prepared from myristoyl chloride 53. Ester 16 was condensed with carboxylic acid 52 under Yamaguchi conditions.(13d) Protected fatty acid side chain 54 was successfully converted into the fatty acid fragment of caprazamycin A (4), which had the same stereochemistry as the natural product, in the presence of Pd/C under a hydrogen atmosphere. Me Me

Me BnOH

O

NMe 2

OMe

O

O

HO

19

O N

NH (10 mol%) O S O

Me

O

86%, 92% ee 17

CF 3

N

H2, Pd/C 92%

nC12H25 53 LDA, THF

Cl

BnOAc O

O

nC12H25

OBn 18

then nBuLi Me O OH MeO

OMe OMe 15 48% ( = 4:1)

CF 3

[Desymmetrization]

O

Cl

OBn

Me 51 (R = Bn) 52 (R = H) MeO

O

OR

O

O OMe OMe

H2 (S)-BINAP-RuBr2 (1.6 mol%) nC12H25

Me

OH O

OBn 16 2,4,6-trichlorobenzoyl 61% chloride, DMAP

48%, 94%ee (2 steps)

54 (R' = Bn) 4 (R' = H)

O Me MeO

O

O

O OMe OMe

O Me

Ester 58b was treated with zinc and AcOH to reductively remove the Troc group (Scheme 9). The resultant secondary amine was subjected to reductive amination followed by removal of the TES group to furnish N-methylated compound 59 in 66% yield. The glutaric monoester unit 52 was then successfully introduced to secondary alcohol 59 under Yamaguchi conditions. This stepwise method for introducing the fatty acid side chain was robust owing to no decomposition of the unstable structure and no epimerization. Therefore, this route would be applicable to introducing the fatty acid side chains of not only caprazamycins, but related liponucleoside antibiotics such as liposidomycins and sphaerimicins. 3. Total synthesis of caprazol (2) and caprazamycin A (1) With an established route for introducing the fatty acid side chain in hand, we next focused on constructing a 1,4-diazepanone

Me Pd black EtOH-HCO2H 96%

O

dimethoxybenzyl (DMB)-protected -hydroxy carboxylic acid 55a was attempted.(37) However, reactions using EDCI, DCC, or PyBOP did not afford desired coupling product 56, with aldehyde 57 observed as a byproduct produced by a retro-aldol reaction. In contrast, the reaction of Troc-protected 1,4diazepanone 41b with DMB-protected -hydroxy carboxylic acid 55a using EDCI proceeded smoothly, giving desired coupling product 58a in excellent yield. For subsequent transformations, including protecting group removal, triethylsilyl (TES)-protected -hydroxy carboxylic acid 55b was employed in this condensation reaction, affording desired ester 58b in 62% yield. These results indicated that compound 41b was more reactive than 41a in this transformation, despite having the same conformation. Our DFT calculations suggested that the enhanced reactivity of 41b might be due to the presence of a hydrogen bond between the hydroxy and Troc groups (Figure 5).

OR'

O

[Fatty acid]

Scheme 8. Synthesis of fatty acid side chain 4.

With fatty acid side chain 4 and model 1,4-diazepanones 41a and 41b in hand, our attention turned to introducing the fatty acid side chain onto the 1,4-diazepanone core. Initially, the direct coupling of 4 onto model 1,4-diazepanone 41a was investigated (Scheme 9). When using EDCI, DCC, or PyBOP, the reaction gave a complex mixture.(36) To avoid undesired elimination of the -alkoxyester unit, condensation with 2,4-

core bearing amino-ribose and uridine moieties and introducing the side chain to achieve a total synthesis of caprazamycin A. Glycosylation of syn--hydroxyamino acid derivatives 10 with compound 9 proceeded in a β-selective manner under the conditions reported by Matsuda and Ichikawa (Scheme 10).(12) Reduction of the azide in coupling product 60, followed by protection of the resulting amine with a Cbz group and methyl ester hydrolysis afforded carboxylic acid 8. Carboxylic acid 8 was coupled with anti--hydroxyl acid derivative 7a, in which the secondary alcohol was protected as a TBS ether, using Ghosez’s reagent(34) via acid chloride formation. Selective TBS group removal from the primary alcohol of 61a gave cyclization precursor 6a. To investigate the Mitsunobu cyclization, compound 6b was also synthesized from carboxylic acid 8 and anti--hydroxyl acid derivative 7b using a similar sequence. No -elimination or epimerization were observed in these transformations.



Page 10 of 18

Model study (1) Me

O O

Me

O

OH

O

O OMe OMe

MeO

Me

HO EtO 2C

O

4

Me

O DMBO

OH

(DMB = 2,4-dimethoxybenzyl)

HO

decomp.

41a

EDCI DCC PyBOP

EtO 2C

HO

RO

OH

R = DMB (55a) R = TES (55b)

EtO 2C

N

MeO

O

NMe OBn

EtO 2C

EtO

R = DMB, quant. R = TES, 62%

MeO

[Troc group promoted esterification] O

O

41a (R = Me)

O

O

66% ( 4 steps)

41b (R = Troc)

Figure 5. Conformations of compounds 41a and 41b calculated by Gaussian ‘09 at the B3LYP/6-31G(d) level of theory (DFT).

Next, we focused on construction the 1,4-diazepanone skeleton using a Mitsunobu reaction. Initially, the intramolecular Mitsunobu reaction of compound 6b, bearing a secondary alcohol protected as a p-methoxybenzyl (PMB) ether, was attempted. Although the cyclization of simple model compound 42 proceeded smoothly (Scheme 7), the reaction of 6b did not give desired cyclization product, even when diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) were employed in the presence of PPh3. Mass spectrometry analysis indicated that byproduct 63 was generated in this reaction through an intermolecular SN2 reaction with hydrazine-1,2-dicarboxylate produced by the

NMe OBn

NMe OBn N Me O

EtO 2C

N Me O 57

56

O R = DMB (58a) R = TES (58b)

RO

O

N

Troc OBn

N Me O

EtO 2C

1. Zn, AcOH 2. (CH2O)n, AcOH NaBH(OAc)3 3. HF·Py, THF

(R = TES)

O

Me

2,4,6-trichlorobenzoyl chloride, DMAP, Et3N

Hydrogen bond (OH and Troc)

N Me O

EtO 2C

HO

NR OBn

41a (R = Me) 41b (R = Troc)

OH

O Me OMe OMe 52

NMe OBn

O

EDCI, DMAP

N Me O

O Me O N OMe EtO 2C Me O OMe 40 [Western part of caprazamicins]

N Me O

O

Me

Scheme 9. Introduction of fatty acid onto diazepanone 41.

HO

Me

O

40

decomp.

Troc OBn

O O

O OMe OMe

O [Retro-aldol product]

Me O

O

DMBO

N Me O

41b

Me

O

Me

41a

O

O

MeO

O

NMe OBn

Model study (2)

Me

Me

N Me O

O

55a

Me

O

Me NMe OBn

59

O

EtO 2C

NMe OBn N Me O

reduction of DEAD or DIAD. These results indicated that the intermolecular SN2 reaction of intermediate 64 was preferred over the desired intramolecular SN2 reaction. To suppress this side reaction, we employed sterically bulkier substrate 6a bearing a TBS group adjacent to the primary alcohol. As expected, the reaction with DIAD afforded cyclized product 62 in 70% yield. Furthermore, using di-tert-butyl azodicarboxylate (DBAD), which is bulkier than DIAD, improved the yield to 75%. By increasing the bulkiness of both the substrate and reagent, the undesired intermolecular SN2 reaction was suppressed to afford the 1,4-diazepanone product. Before introducing the fatty acid side chain, cyclized product 62 was converted into protected caprazol 5 to facilitate the final global deprotection (Scheme 10). After removing the pNs group, a Troc group was introduced to afford compound 65 in 58% yield over two steps. Two acetal groups were carefully hydrolysed under acidic conditions and the obtained tetraol was converted to a Cbz carbonate, followed by treatment under acidic conditions to remove the TBS group. To confirm the stereochemistry of protected caprazol 5, it was converted to caprazol (2). Troc group removal followed by reductive amination gave a tertiary amine, followed by treatment with Pd black in the presence of formic acid to give caprazol (2), which had spectra data identical to those reported previously.(12d,e,13c)


Page 11 of 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


H BOM N3 O N

O OH

pNsHN MeO 2C

O

N

O O

O

Et Et

PMBO

O

pNs

HN

O

O

RO 2C

NH N

O

O

O

Me Me

Et Et

O NHCbz

O

Ph 3P O O BOM pNs N O O PMBO O N O N BnO 2C N Me O H O O Sterically less hindered Me Me 64

NHCbz

O OH TBSO BnO 2C

O

pNs

HN

Et Et

 Ph3P=O

O

NHCbz O O NCO 2R BOM pNs N O O PMBO O HN O N BnO 2C N Me O H O O (R = Et or iPr) Me Me RO 2CHN

BOM N O

O

O O

N Me O H

N

O

N O

O

CSA MeOH/DCM 68% (R = TBS)

Me Me

3HF·Et3N 77% (R = PMB)

Me

N

7a (R = TBS) Cl 7b (R = PMB)

NMe 2 [gram scale] Et Et

O NHCbz O O OTBS BOM pNs N O O O HN O N N Me O H O O

RO BnO 2C

Me Me

[gram scale]

61a (R = TBS): 46% (3 steps) 61b (R = PMB): 25% (3 steps)

CO 2iPr (DIAD) PPh3 70% or PhMe, 0 °C N CO 2tBu (DBAD) tBuO2C N 75% Et O Substrate and Et NHCbz Reagent 1. K2CO3 O O controlled PhSH BOM pNs 73% N O O TBSO O N O N 2. TrocCl BnO 2C N H DMAP Me O 79% O O 62 (desired) Me Me

iPrO2C

NHMe

aq. NaHCO3, DCM Me

O

OTBS

BnO 2C

H

or

1.45 g O prepared

N

Et Et

O NHCbz

O Troc O N

TBSO BnO 2C

O

BOM N O

O O

N

N Me O H O

O

65 Me Me

CbzO NHCbz

CbzO [No desired product]

BOM N O

O

O

RO

O

6a

PPh3 PhMe, 0 °C

O

8 Me Me

[Intramolecular Mitsunobu reaction]

CO 2R

NHCbz

O

[gram scale]

Et Et

PMB vs. TBS

O

BOM 1. PPh3 N O O O then CbzCl pNsHN 2. Ba(OH)2 O N HO 2C H

Me Me

DEAD (R = Et) or DIAD (R = iPr)

RO 2C

MeO 2C

N

N Me O H

N

pNsHN

BOM N O

O O

N

O

NHCbz

6b RO 2C

O

Et Et

N3

O O

OH

O

BF3·Et2O, 71% [-Selective Glycosylation] [gram scale] 60

10 Me Me

BnO 2C

O

9 Et Et

H

Et Et

F

O

HO BnO 2C

O

Troc O N

O O

N Me O H CbzO

BOM N O N

1. pTsOH, MeOH, 50 °C, 41% 2. CbzCl, DMAP 3. pTsOH, MeOH, 60 °C 71% (2 steps)

OCbz

HO

Protected caprazol (5) 1. Zn, AcOH 2. (CH2O)n, NaBH(OAc)3 quant. (2 steps) 3. Pd black, EtOH/HCO2H = 10:1, 46%

HO HO

NH 2 O

O HO 2C

N Me O H HO

H N

O

NMe O

O

N OH

Caprazol (2)

63 (undesired)

Scheme 10. Investigation of Mitsunobu reaction and synthesis of caprazol (2).

To complete the first total synthesis of caprazamycin A (1), we carefully applied model studies to couple protected caprazol 5 with fatty acid side chain 55b (Scheme 11). Condensation of 5 with 55b using EDCI successfully proceeded to afford the desired acylated product without undesired side reactions, such as -elimination, epimerization, and retro-aldol reaction on the 1,4-diazepanone. After removing the Troc group in the

presence of zinc and acetic acid, the resultant carbamic acid intermediate was treated with acetic acid to give compound 66 via decarboxylation. Reductive amination of secondary amine 66 was followed by TES group removal to afford corresponding alcohol 67. Yamaguchi conditions(13d) were applied to introduce the fatty acid side chain 52 containing rhamnose. Although the reaction



CbzHN CbzO CbzO

O

Troc O N

HO

O O

BnO 2C

BOM O N

N Me O H CbzO

N

O

nC12H25 55b

TESO

OCbz

NHCbz

O CbzO

Me Me MeO

O

O

CbzO

NHCbz O

O N Me O H CbzO

BOM N O

O

NMe O BnO 2C

O

O

NMe O

O

BOM N O

O N O Me O BnO2C OMe N H O Me OMe CbzO OCbz Protected caprazamycin A (68) Easily reduced CbzO

N

TESO

O

O O

NH

O BnO 2C

1. (CH2O)n, NaBH(OAc)3 AcOH

BOM N O

O

2. HF·Py 43% (5 steps)

N

N Me O H CbzO

OCbz 66

Me MeO

O

O

OH

O Me OMe OMe 52 Cl

Cl

O

O CbzO

nC12H25

OH O

98%

O

O

Cl

O BnO 2C

Cl DMAP, Et3N 64%

N Me O H CbzO

O

Me O

O

O

O OMe OMe

MeO

[Global deprotection in the presence of the olefin]

N OCbz

67

HO

Me

BOM N O

O

NMe O

[Yamaguchi esterification]

Pd black EtOH/HCO2H = 20:1

NHCbz

CbzO

Pd source, H2 several solvent All failed

OCbz

69 (undesired)

O CbzO

nC12H25

[Troc group promoted esterification] CbzO

O

OH

2. Zn, AcOH, 50 °C 3. AcOH, ClCH2CH2Cl

Protected caprazol (5)

NHCbz

CbzO

1. EDCI, DMAP

Page 12 of 18

Me

O

H 2N

HO

O

O

H N

O

NMe O O

O

N

HO 2C

N Me O H HO Caprazamycin A (1)

OH

Scheme 11. The first total synthesis of caprazamycin A (1).

afforded protected caprazamycin A (68), byproduct 69 was readily formed through -elimination under these conditions. Therefore, the amounts of Et3N and 4-dimethylaminopyridine (DMAP) were reduced, and the reaction time was shortened. As a result, protected caprazamycin A (68) was obtained in 64% yield. Finally, conditions for the global deprotection of five Cbz, one BOM, and one Bn groups in the protected caprazamycin A (68) while avoiding reduction of the uracil olefin were investigated. Using 10% Pd/C under a hydrogen atmosphere removed the protecting groups, but also resulted in olefin hydrogenation. Although various palladium (Pd) catalysts, including 5% Pd/C, Pd/C(en), and Pd(OH)2/C, in the presence of various hydrogen sources (H2, cyclohexadiene, and formic acid) were examined, none were able to suppress olefin reduction. In contrast, treatment with EtOH/formic acid (20:1, v/v) in the presence of Pd black resulted in a near-quantitative clean deprotection without olefin reduction. After careful neutralization, the spectral data, including NMR (DMSOd6/D2O, 20:1) and HRMS data, of the synthetic sample were identical to those of the natural product.(1) Therefore, the first total synthesis of caprazamycin A (1) was successfully accomplished. The NMR spectra of caprazamycin A (1) were concentration- and pKa-dependent (Scheme 12). When NMR spectra of 1 were measured using DMSO-d6/D2O/DCO2D

(20:1:1), the carboxylic acid -proton in 1 was shifted downfield compared with that measured in HO O

Me Me MeO

O

O

O OMe OMe

O Me

O O 2C

N H Me O H HO ca. 3.8 ppm Caprazamycin A in DMSO-d6/D2O = 20:1

O O

O

O OMe OMe

O Me

O

O

DO 2C

HO

H N

O O

O

Me

MeO

ND 3 O

NMe O

DCO2D

Me

HO

N OH

2DCO2 ND 3

HO O D H N O NMe O O N

N H Me O H HO OH ca. 4.6 ppm Caprazamycin A in DMSO-d6/D2O/DCO2D = 20:1:1

Scheme 12. 1H NMR spectrum of caprazamycin A (1).


O

O

Page 13 of 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


DMSO-d6/D2O (20:1). This indicated that caprazamycin A was in zwitterion form in DMSO-d6/D2O, but had a protonated carboxylic acid in the presence of formic acid. Conclusions We have developed a diastereoselective aldol reaction of diethyl isocyanomalonate 13 and phenylcarbamate 21 for the synthesis of -hydroxy amino acid derivatives. Thiourea catalyst 14 effectively obtained the desired 5’S-isomer 11a in the aldol reaction of aldehyde 12 bearing an isopropylidene acetal moiety. The resultant aldol products were readily converted into syn--hydroxy amino acid derivatives 10, 38, and 39 bearing several protecting groups. The 1,4-diazepanone core structure of caprazamycin A was obtained using a Mitsunobu reaction. A synthetic route for introducing a fatty acid side chain was established using a stepwise sequence. Finally, we achieved the first total synthesis of caprazamycin A by identifying conditions for global deprotection without hydrogenation of the olefin in the uridine unit. These results and the established synthetic route will guide the synthesis of related liponucleoside antibiotics bearing fatty acid side chains, including liposidomycins and spaerimicin A, and investigations into the synthesis of a related natural product are currently underway in our laboratory.

ASSOCIATED CONTENT

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Supporting Information. Experimental procedures, analytical data (1H and 13C NMR, MS) for all new compounds as well as summaries of unsuccessful approaches. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION Corresponding Authors E-mail: [email protected] (C. T.). E-mail: [email protected] (Y. T.).

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Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS

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This work was supported by a Grant-in-Aid for Scientific Research (S) (JSPS KAKENHI no. JP16H06384, Y.T.), a Grant-in-Aid for JSPS fellows (H.N.) and JSPS KAKENHI (Grant No. JP17H05051, C.T.), and JSPS KAKENHI (Grant No. JP18H04407, C.T.) in the Middle Molecular Strategy.

REFERENCES (1)

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Diastereoselective syntheses of α-amino-β-hydroxyesters precursors of the ribosyl-diazepanone core of the liposidomycins. Tetrahedron Lett. 2003, 31, 2781; s) Knapp, S.; Morriello, G. J.; Doss, G. A. Synthesis of the Liposidomycin Diazepanone Nucleoside. Org. Lett. 2002, 4, 603; t) Gravier-Pelletier, C.; Milla, M.; Merrer, Y. L.; Depezay, J. C. Liposidomycins − Synthetic Studies Towards the Ribosyldiazepanone Moiety. Eur. J. Org. Chem. 2001, 16, 3089; u) Knapp, S.; Morriello, G. J.; Nandan, S. R.; Emge, T. J.; Doss, G. A.; Mosley, R. T.; Chen, L. Assignment of the Liposidomycin Diazepanone Stereochemistry. J. Org. Chem. 2001, 66, 5822; v) Kim, K. S.; Ahn, Y. H. Synthesis of the diazepanone-nucleoside portion of liposidomycins by aldol reaction of the enolate of diazepanone with a nucleoside 5’aldehyde. Tetrahedron: Asymmetry 1998, 9, 3601; w) Merrer, Y. L.; Gravier-Pelletier, C.; Gerrouache, M.; Depezay, J. C. Access to enantiopure ribosyl-diazepanone core of liposidomycins. Tetrahedron Lett. 1998, 39, 385; x) Kim, K. S.; Cho, I. H.; Ahn, Y. H.; Park, J. I. Synthesis of the 1,4diazepan-2-one moiety of liposidomycins. J. Chem. Soc. Perkin Trans. 1 1995, (26), 1783; y) Knapp, S.; Nandan, S.; Resnick, L. Synthesis of the liposidomycin diazepanone. Tetrahedron Lett. 1992, 33, 5485. (12) a) Ichikawa, S. Function-Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products? Chem. Rec. 2016, 16, 1106; b) Ichikawa, S. Fine Synthetic Nucleoside Chemistry Based on Nucleoside Natural Products Synthesis. Chem. Pharm. Bull. 2008, 56, 1059. c) Hirano, S.; Ichikawa, S.; Matsuda, A. Synthesis of Caprazamycin Analogues and Their Structure−Activity Relationship for Antibacterial Activity. J. Org. Chem. 2008, 73, 569; d) Hirano, S.; Ichikawa, S.; Matsuda, A. Development of a Highly β-Selective Ribosylation Reaction without Using Neighboring Group Participation: Total Synthesis of (+)-Caprazol, a Core Structure of Caprazamycins. J. Org. Chem. 2007, 72, 9936; e) Hirano, S.; Ichikawa, S.; Matsuda, A. Total Synthesis of Caprazol, a Core Structure of the Caprazamycin Antituberculosis Antibiotics. Angew. Chem. Int. Ed. 2005, 44, 1854. (13) a) Takeuchi, T.; Abe, H.; Watanabe, T.; Shibasaki, M. Catalytic asymmetric synthesis of CPZEN-45. Tetrahedron Lett. 2016, 57, 2901; b) Abe, H.; Gopinath, P.; Ravi, G.; Wang, L.; Watanabe, T.; Shibasaki, M. Synthesis of caprazamycin B. Tetrahedron Lett. 2015, 56, 3782; c) Gopinath, P.; Wang, L.; Abe, H.; Ravi, G.; Masuda, T.; Watanabe, T.; Shibasaki, M. Catalytic Asymmetric Total Synthesis of (+)-Caprazol. Org. Lett. 2014, 16, 3364; d) Gopinath, P.; Watanabe, T.; Shibasaki, M. Studies on Catalytic Enantioselective Total Synthesis of Caprazamycin B: Construction of the Western Zone. J. Org. Chem. 2012, 77, 9260; e) Gopinath, P.; Watanabe, T.; Shibasaki, M. Catalytic Enantioselective Desymmetrization of meso-Glutaric Anhydrides Using a Stable Ni2-Schiff Base Catalyst. Org. Lett. 2012, 14, 1358. (14) a) Nakamura, H.; Yoshida, T.; Tsukano, C.; Takemoto, Y. Synthesis of CPZEN-45: Construction of the 1,4-Diazepin-2one Core by the Cu-Catalyzed Intramolecular Amidation of a Vinyl Iodide. Org. Lett. 2016, 18, 2300; b) Nakamura, H.; Tsukano, C.; Yasui, M.; Takemoto, Y. Total Synthesis of (−)Caprazamycin A. Angew. Chem. Int. Ed. 2015, 54, 3136; c) Tsukano, C.; Yokouchi, S.; Girard, A. L.; Kuribayashi, T.; Sakamoto, S.; Enomoto, T.; Takemoto, Y. Platinum catalyzed 7-endo cyclization of internal alkynyl amides and its application to synthesis of the caprazamycin core. Org. Biomol. Chem. 2012, 10, 6074; d) Girard, A. L.; Enomoto, T.; Yokouchi, S.; Tsukano, C.; Takemoto, Y. Control of 6Exo and 7-Endo Cyclizations of Alkynylamides using


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Journal of the American Chemical Society Platinum and Bismuth Catalysts. Chem. Asian J. 2011, 6, 1321. Kan, T.; Fukuyama, T. Ns strategies: a highly versatile synthetic method for amines. Chem. Commun. 2004, (0), 353. Sakamoto, S.; Kazumi, N.; Kobayashi, Y.; Tsukano, C.; Takemoto, Y. Asymmetric Synthesis of Trisubstituted Oxazolidinones by the Thiourea-Catalyzed Aldol Reaction of 2-Isocyanatomalonate Diester. Org. Lett. 2014, 16, 4758. For recent reviews of thiourea-based catalysts, see: a) Connon, S. J. Organocatalysis Mediated by (Thio)urea Derivatives. Chem. Eur. J. 2006, 12, 5418; b) Doyle, A. G.; Jacobsen, E. N. Small-Molecule H-Bond Donors in Asymmetric Catalysis. Chem. Rev. 2007, 107, 5713; c) Connon, S. J. Asymmetric catalysis with bifunctional cinchona alkaloid-based urea and thiourea organocatalysts. Chem. Commun. 2008, (0), 2499; d) Zhang, Z.; Schreiner, P. R. (Thio)urea organocatalysis—What can be learnt from anion recognition? Chem. Soc. Rev. 2009, 38, 1187; e) Takemoto, Y. Development of Chiral Thiourea Catalysts and Its Application to Asymmetric Catalytic Reactions. Chem. Pharm. Bull. 2010, 58, 593. (f) Auvil, T. J.; Schafer, A. G.; Mattson, A. E. Design Strategies for Enhanced Hydrogen‐ Bond Donor Catalysts. Eur. J. Org. Chem. 2014, 2014, 2633. Part of this work has been published in preliminary communications, see refs. 14a and 14b. a) Cesa, M. C.; Rinz, J. E.; Kopp, T. T. Aryl oxime derivatives of hydantoins. U.S. patent, 1987, US 4705864 A; b) Cesa, M. C.; Rinz, J. E.; Klopman, G.; Kopp, T. T. N,N'disubstituted ureas. U.S. patent, 1988, US 4740611 A. Wang, R.; Steensma, D. H.; Takaoka, Y.; Yun, J. W.; Kajimoto, T.; Wong, C.-H. A search for pyrophosphate mimics for the development of substrates and inhibitors of glycosyltransferases. Bioorg. Med. Chem. 1997, 5, 661. a) Danishefsky, S. J.; DeNinno, M. P.; Phillips, G. B.; Zelle, R. E.; Lartey, P. A. On the communication of chirality from furanose and pyranose rings to monosaccharide side chains: anomalous results in the glucose series. Tetrahedron 1986, 42, 2809; b) Danishefsky, S. J.; DeNinno, S. L.; Chen, S.-H.; Boisvert, L.; Barbachyn, M. Fully synthetic stereoselective routes to the differentially protected subunits of the tunicamycins. J. Am. Chem. Soc. 1989, 111, 5810; c) Chen, X.; Wiemer, D. F. -Phosphono Lactone Analogues of Cytidine and Cytosine Arabinoside Diphosphates: Synthesis via Ring Closing Metathesis. J. Org. Chem. 2003, 68, 6597. Ichikawa and coworkers recently reported controlling diastereoselectivity in the Mukaiyama aldol reaction of compound 12 using Lewis acids, see Yamamoto, K.; Yakushiji, F.; Matsumura, T.; Ichikawa, S. Total Synthesis of Tunicamycin V. Org. Lett. 2018, 20, 256. The transition states were also calculated with several different functionals, including dispersion correction. See the Supporting Information for the details of computational studies. Compound 25 was prepared by IBX oxidation of a known BOM-protected uridine, see: Silva, D. J.; Sofia, M. J. Novel carbohydrate scaffolds. Assembly of a uridine–mannose scaffold based on tunicamycin. Tetrahedron Lett. 2000, 41, 855. Compound 26 was prepared from uridine in five steps: (i) TBS protection of the 5’-hydroxy group; (ii) BOM protection of the nitrogen atom; (iii) TIPS protection of the 2’,3’hydroxy groups; (iv) selective removal of the TBS group; and (v) Dess–Martin oxidation. Also see the supporting information. Spork, A. P.; Wiegmann, D.; Granitzka, M.; Stalke, D.; Ducho, C. Stereoselective Synthesis of Uridine-Derived Nucleosyl Amino Acids. J. Org. Chem. 2011, 76, 10083.

(27) For the nucleophilic addition of phosphite to aldehyde 27, Wiemer and coworkers proposed a chelated transition state, in which an attractive electrostatic interaction between silicon and the carbonyl oxygen was postulated; see: Chen, X.; Wiemer, A. J.; Hohl, R. J.; Wiemer, D. F. Stereoselective Synthesis of the 5‘-Hydroxy-5‘-phosphonate Derivatives of Cytidine and Cytosine Arabinoside. J. Org. Chem. 2002, 67, 9331. (28) Ohshima, T.; Iwasaki, T.; Maegawa, Y.; Yoshiyama, A.; Mashima, K. Enzyme-Like Chemoselective Acylation of Alcohols in the Presence of Amines Catalyzed by a Tetranuclear Zinc Cluster. J. Am. Chem. Soc. 2008, 130, 2944. (29) Roberts, T. C.; Smith, P. A.; Cirz, R. T.; Romesberg, F. E. Structural and Initial Biological Analysis of Synthetic Arylomycin A2. J. Am. Chem. Soc. 2007, 129, 15830. (30) a) Arias-Pérez, M. S.; López, M. S.; Santos, M. J. Imidazolepromoted 1,4-migration of the tert-butyldiphenylsilyl group: influence on the selectivity control of the silylation reactions of carbohydrate OH groups. J. Chem. Soc., Perkin Trans. II, 2002, (0), 1549; b) Evans, D. A.; Black, W. C. Total synthesis of (+)-A83543A [(+)-lepicidin A].; J. Am. Chem. Soc. 1993, 115, 4497. (31) a) Noyori, R.; Takaya, H. BINAP: an efficient chiral element for asymmetric catalysis. Acc. Chem. Res. 1990, 23, 345; b) Ratovelomanana-Vidal, V.; Girard, C.; Touati, R.; Tranchier, J. P.; Ben Hassine, B.; Genêt, J. P. Enantioselective Hydrogenation of -Keto Esters using Chiral Diphosphine‐ Ruthenium Complexes: Optimization for Academic and Industrial Purposes and Synthetic Applications. Adv. Synth. Catal. 2003, 345, 261. (32) a) Oh, S. H.; Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin, J.; Song, C. E. A highly reactive and enantioselective bifunctional organocatalyst for the methanolytic desymmetrization of cyclic anhydrides: prevention of catalyst aggregation. Angew. Chem. Int. Ed. 2008, 47, 7872; b) Honjo, T.; Tsumura, T.; Sano, S.; Nagao, Y.; Yamaguchi, K.; Sei, Y. A Chiral Bifunctional Sulfonamide as an Organocatalyst: Alcoholysis of σ-Symmetric Cyclic Dicarboxylic Anhydrides. Synlett, 2009, 20, 3279. (33) a) Mori, K.; Iwasawa, H. Stereoselective synthesis of optically active forms of δ-multistriatin, the attractant for european populations of the smaller european elm bark beet. Tetrahedron, 1980, 36, 87; b) Saito, S.; Bunya, N.; Inaba, M.; Moriwake, T.; Torii, S. A facile cleavage of oxirane with hydrazoic acid in dmf A new route to chiral β-hydroxy-αamino acids. Tetrahedron Lett. 1985, 26, 5309. (34) Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens, A.; Ghosez, L. Synthesis of acyl halides under very mild conditions. J. Chem. Soc., Chem. Commun. 1979, (0), 1180. (35) Taber, D. F.; Deker, P. B.; Fales, H. M.; Jones, T. H.; Lloyd, H. A. Enantioselective construction of heterocycles. Synthesis of (R,R)-solenopsin B. J. Org. Chem. 1988, 53, 2968. (36) Since our total synthesis of caprazamycin A, Shibasaki, Watanabe, and coworkers succeeded in directly introducing the fatty acid side chain using 2-methyl-6-nitrobenzoic anhydride (MNBA) for the total synthesis of caprazamycin B, see: ref. 13b. (37) There are a few reports of the introduction of a simple acyl group into the 1,4-diazepanone ring, see: a) Hirano, S.; Ichikawa, S.; Matsuda, A. Structure–activity relationship of truncated analogs of caprazamycins as potential antituberculosis agents. Bioorg. Med. Chem. 2008, 16, 5123; b) Mravljak, J.; Monasson, O.; Al-Dabbagh, B.; Crouvoiseire, M.; Bouhss, A.; Gravier-Pelletier, C.; Merrer, Y. L. Synthesis and biological evaluation of a diazepanone-based library of liposidomycins analogs as MraY inhibitors. Eur. J. Med. Chem. 2011, 46, 1582; c) also see refs. 11i and 12c.




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Table of Contents (TOC) [cyclic peptide ring] [unstable fatty acid]

Me

O Me MeO

O

O

O

O OMe OMe

O

NH 2

HO HO NMe O

O O

H N

O N N Me O H [-hydroxy--aminoacid] HO OH Caprazamycin A [The full details] Me

O

HO 2C


O


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Total Synthesis of Caprazamycin A - ACS Publications - American

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