BÀI TẬP LẤY ĐIỂM CHUYÊN CẦN

CHUYÊN ĐỀ PHÂN TÍCH TỔNG HỢP TOÀN PHẦN

Giới thiệu: Đây là một bài tập lớn để làm theo nhóm (tùy chọn) được thiết kế theo phong cách nghiên
cứu/đọc-hiểu báo khoa học kết hợp với giải bài tập lý thuyết. Hoạt động này được thiết kế nhằm hướng
các em đến gần với cách nhìn của một nhà Hóa học thật sự với tư duy khoa học đi từ kiến thức có sẵn.

Các em có thể trả lời bằng cách viết hay vẽ bằng tay hay dùng phần mềm Chemdraw. Các em trình bày
tên, lớp và trường theo mẫu bên dưới và gửi bài làm của mình dưới dạng file PDF về email:
minhhuy.up2012@gmail.com.

Hạn chót: 24/11/2023

Các em có thể làm bài cá nhân hoặc theo nhóm tối đa 4 người. Các em có thể bổ sung trích dẫn (sách, báo
khoa học,…) nếu cần. Mỗi em trong nhóm sẽ được tính điểm như nhau. Ví dụ: nhóm được 20 điểm thì
mỗi em trong nhóm đều được 20 điểm chuyên cần.

Giáo viên: Lý Minh Huy

Tên học sinh Trường Lớp

Các thử thách sẽ có định dạng GIỐNG HỆT NHAU nhưng độ khó tăng dần từ thử thách tăng dần từ thử
thách 1 đến 3. Mỗi thử thách sẽ có nhiệm vụ như sau:

a. Nhóm học sinh phải đọc các đoạn trích từ bài báo khoa học (bằng tiếng Anh) để xác định cấu
trúc/cấu tạo phù hợp để điền vào chỗ trống. Mỗi cấu trúc/cấu tạo đúng sẽ được 1 điểm. Mỗi thử
thách sẽ có 10 ô trống tương ứng với 10 điểm.
b. Nhóm học sinh dựa vào nội dung và cấu tạo đã điền vào ô trống để trả lời một số câu hỏi tổng quan
về: cơ chế phản ứng, đại cương hóa học, nguyên lý cơ bản của phản ứng hóa học,… Mỗi câu hỏi có
tổng là 2 điểm, mỗi thử thách sẽ có 5 câu hỏi.
c. Nhóm học sinh phải viết một đoạn văn ngắn (300 – 450 chữ) để nêu ưu/nhược điểm, phản biện, ý
kiến của mình về đề tài nghiên cứu trong thử thách đã tham gia. Ví dụ: chiến thuật của nhóm tác giả
sử dụng quá nhiều nhóm bảo vệ/phản ứng oxid hóa khử, hoặc đưa ra cách khác tổng hợp nhanh hơn
và tối ưu hơn,… Mỗi đoạn văn ngắn được tối đa 5 điểm.

Điểm tối đa của ba thử thách là 75 điểm, tương ứng với 25 điểm chuyên cần (trung bình cộng của ba thử
thách), được cộng thẳng vào điểm chuyên cần của tháng 12. Các thử thách sẽ trở thành một trong những
nội dung học của chuyên đề Tổng hợp toàn phần 2023.
 Thử thách 1: Tổng hợp toàn phần Trigoxyphins K và L

Đoạn trích trong báo khoa học và chuỗi phản ứng:

“This new sequence began with Grignard addition to Weinreb amide 12 and then silylation of the so-
formed ketone 13 in readiness for 1,4-addition to methyl vinyl ketone (MVK). This step (→ 14) was most
effectively achieved by a modification of Loh’s method with indium(III) chloride. For this application, to
avoid extensive tarring of the furan derivative, the reaction was moderated by including a solvent and
keeping the catalyst loading to 2 mol % (cf. reported conditions: neat and 20 mol % catalyst, respectively).
Intramolecular aldol condensation under classical conditions gave cyclohexenone 15, which was
efficiently methylenated (→ 16) and aromatized under basic conditions to generate phenol derivative 17.
The crucial acid-catalyzed cyclization to close the B ring was expected to require carefully chosen
conditions because of the natural tendency of furans to decompose in the presence of both protic and
Lewis acids, which, here, would be exacerbated by attachment to a free phenol. The lack of simple alkenes
as electrophiles in Tanis’ work and a 0% yield in a related cyclization gave further cause for concern. Noting
the particular effectiveness of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as an additive in promoting
camphor sulfonic acid (CSA)-catalyzed tandem cyclizations, Spivey’s reported conditions were applied to
intermediate 17. In the event, cyclization progressed steadily to give tricyclic phenol 18, with the only
complication arising from competing deprenylation of the substrate. Trigoxyphins L and K were then
obtained by the singlet oxidation and Luche reduction steps used previously.”

Route 1:

“In this third approach, the A ring would be formed as the final step from an appropriately functionalized
2-benzosuberone that, in turn, would be obtained from the ring expansion of known tetralone derivative
19. This ketone, obtained in three steps (∼50% yield) from 2-methylanisole, was dimethylated (→ 20) and
converted into the corresponding alkene 21 by Wittig methylenation under standard conditions. In model
studies of the ring expansion of 1-methylene-1,2,3,4-tetrahydronaphthalene and its 2,2-dimethyl
derivative, Silva’s modification of Koser’s method with [hydroxy(tosyloxy)iodo]benzene (HTIB) was found
to work well. With alkene 21, however, isolated yields were much reduced because of the ease of
oxidation of the methylene group flanked by carbonyl functionality and an electron-rich aromatic system
in the product. Efficient reaction was restored by replacing Silva’s combination of iodobenzene and meta-
chloroperbenzoic acid (mCPBA) with a slight excess of (diacetoxy)iodobenzene, affording cycloheptanone
derivative 22. The reaction conditions for a one-step method using glyoxylic acid to introduce the
hydroxybutenolide functionality required for trigoxyphin L worked well in the above-mentioned model
study; however, this process proved too harsh for ketone 22, and complex reaction mixtures resulted.
Eventually, the most direct solution was found in enolate alkylation and then treatment of the so-formed
keto ester 23 with boron tribromide. This latter reagent not only removed the phenolic O-methyl
substituent as expected but also promoted lactonization and alkene isomerization to deliver trigoxyphin
K directly. In a reversal of the final end-game steps in the previous two routes, trigoxyphin K was converted
into trigoxyphin L by oxygenation of the extended enolate formed under reversible conditions.”

Route 2:

Các câu hỏi về tổng quan:

1. Trong phản ứng từ 13 sang 14, chuyện gì có thể xảy ra nếu sử dụng quá nhiều InCl3? Giải thích.
2. Trong phản ứng từ 17 sang 18, những phản ứng phụ nào có thể xảy ra ngoài phản ứng đóng vòng 7
cạnh?
3. Đề nghị cơ chế hoàn chỉnh cho phản ứng từ 18 sang 2.
4. Đề nghị cơ chế hoàn chỉnh cho phản ứng từ 2 sang 1 (sử dụng NaBH4/CeCl3).
5. Đề nghị cơ chế hoàn chỉnh cho phản ứng từ 21 sang 22.

Hãy viết một đoạn văn ngắn phản biện đề tài này.

Gợi ý:

- So sánh hai phương pháp (số bước, hiệu suất,…).

- Bàn về phản ứng tạo hệ thơm.
- Bàn về các phản ứng chìa khóa tạo thành cấu trúc.
 Thử thách 2: Phần đầu của tổng hợp toàn phần Vilmoracotine

Đoạn trích trong báo khoa học và chuỗi phản ứng:

“Our forward synthesis commenced with aldehyde 8, which was prepared on a decagram scale based on
our previously reported procedures. Subjecting 8 to a lithium species generated in situ from bromide 9
and n-BuLi furnished the desired adduct 10 as a pair of inseparable diastereomers (91% combined yield,
1:1 d.r.). Upon treatment with PhI(OAc)2 in methanol, phenol 10 rapidly underwent a tandem oxidative
dearomatization/Diels–Alder dimerization process; heating the resultant cycloadduct (see the Supporting
Information) at 180 °C led to a pair of separable diastereomers 11a (40% yield) and 11b (41% yield)
through a retro Diels–Alder/IMDA cascade with exclusive endo-selectivity. The undesired diastereomer
11b with a C1−β-OH group was determined by its NOE difference spectroscopy, which could be recycled
to 11a via an oxidation and selective reduction sequence. Thus, 11a was prepared on a multigram scale
with a 62% overall yield from 10. Methylation of the C1 hydroxyl group using NaH/MeI, followed by
desilylation (with TBAF) and oxidation (with IBX), converted 11a into 12. Subsequently treating aldehyde
12 with t-BuOK and MeI provided 13 (89% yield) as the sole product, in which MeI approached the in situ
generated enloate from the sterically less hindered face, thereby installing the requisite C4 quaternary
stereogenic center. At this point, the nitrogen atom was introduced by reductive amination of aldehyde
13 using EtNH2·HCl and NaBH3CN, which was followed by protection of the resultant secondary amine
with the Boc group by adding NaOH/(Boc)2O in the same pot, thus delivering 14 with a 90% yield. Further
functionality manupulations involving reduction of C10 ketone, deprotection of the adjacent acetal, and
reductive removal of the C10 hydroxyl group transformed 14 into 7 (62% yield over 3 steps).”

a
Reagents and conditions: (a) n-BuLi, THF, 0 to −78 °C, 91%, 1:1 d.r. (b) PhI(OAc)2, NaHCO3, MeOH, 23 °C. (c)
mesitylene, 180 °C, 40% (11a from 10), 41% (11b from 10). For the conversion of 11b into 11a: (1) DMP, NaHCO3,
CH2Cl2, 23 °C, 93%. (2) NaBH(OMe)3, THF, −30 °C, 58% (11a), 14% (11b). (d) NaH, MeI, THF, 0 to 30 °C, 85%. (e) TBAF,
THF, 23 °C, 93%. (f) IBX, DMSO, 23 °C, 90%. (g) t-BuOK, MeI, THF, −10 °C, 89%. (h) EtNH2·HCl, Et3N, HOAc, MeCN, 23
°C; then NaBH3CN, 23 °C; then NaOH (aq.), (Boc)2O, 23 °C, 90%. (i) LiAlH4, THF, 23 °C. (j) p-TsOH, MeOH/CH2Cl2 (10:1),
23 °C. (k) SmI2, MeOH, 23 °C, 62% (3 steps). (l) O 3, MeOH, −78 °C; then FeSO4·7H2O, 4-methoxybenzenethiol, −78 to
23 °C, 77%. (m) TFA, CH2Cl2, 40 °C, 90%. (n) LDA, NCCO2Me, THF, −78 °C. (o) Cs2CO3, MVK, THF, 0 to 23 °C, 62% (2
steps). (p) KHMDS, THF, −78 °C, 85%. (q) TiCl4, MeOH, Et3N, 23 °C, 80% (93% brsm). (r) LiAlH4, THF, 23 °C. (s) AZADO,
CuCl, bpy, DMAP, MeCN/CH2Cl2 (10:1), air, 23 °C, 88% (2 steps). (t) LDA, (EtO)2P(O)CH2CN, THF, 23 to 50 °C, 93%. (u)
TMSOTf, CH2Cl2, 23 °C, 92%. (v) I2, NaHCO3, THF/H2O (2:1), 0 to 23 °C, 80%. (w) TMP, TBSOTf, THF, −78 °C; then
mesitylene, 150 °C; then p-TsOH, CH2Cl2, 23 °C, 75% (85% brsm). (x) NaBH4, MeOH/THF (1:1), 0 °C. (y) t-BuOK, MeI,
THF, −20 °C, 67% (2 steps). (z) LDA, O2, THF, −78 °C; then SnCl2, H2O, Na2CO3 (aq.), 23 °C, 80%. (aa) LiAlH4, THF, 70 °C.
(ab) AZADO, CuCl, bpy, DMAP, MeCN/CH2Cl2 (10:1), air, 23 °C, 68% (2 steps). Abbreviations: TBS = tert-
butyldimethylsilyl; DMP = Dess–Martin periodinane; TBAF = tetrabutylammonium fluoride; IBX = o-iodoxybenzoic
acid; Boc = tert-butoxycarbonyl; LDA = lithium diisopropylamide; HMDS = 1,1,1,3,3,3-hexamethyldisilazane; AZADO
= 2-azaadamantane N-oxyl; bpy = 2,2′-bipyridyl; DMAP = N,N-dimethyl-4-aminopyridine.

“With tricyclic alkene 7 in hand, the stage was set for investigating the key hydrodealkenylative
fragmentation. Pleasingly, subjection of 7 to the slightly modified conditions (O3, MeOH, −78 °C;
FeSO4·7H2O, 4-methoxybenzenethiol, −78 to 23 °C) based on Kwon’s report resulted in the generation of
the expected aldehyde product 6 in 77% yield on a gram scale. Of note, this method proved to be suitable
for complex substrates, in which an unprotected ketone carbonyl group was compatible. Next, TFA-
promoted Mannich cyclization of aldehyde 6 occurred efficiently to give the tetracyclic product 5 (90%
yield). We sought to perform the above two steps in one pot by directly adding acid to the reaction mixture
of hydrodealkenylative fragmentation, which only afforded a trace amount of the cyclized product 5. On
the other hand, after removal of reaction solvent, treatment of the crude hydrodealkenylation product
with TFA could generate the desired product 5 with a moderate overall yield (35% over two steps). Thus,
the above hydrodealkenylative fragmentation/Mannich cyclization sequence allowed for facile
transformation of a 6/6/6 tricyclic system (i.e., compound 7) into the 6/5/5/6 tetracycle 5 possessing a
highly substituted piperidine unit. We then carried out our synthesis forward to assemble the six-
membered D ring. Installation of a methoxycarbonyl group at the α-position of C8 carbonyl functionality
in 5 using LDA and Mander’s reagent (NCCO2Me), followed by treatment with Cs2CO3 and methyl vinyl
ketone (MVK), afforded 15 (62% yield over two steps) as a single diastereomer. In this transformation,
MVK was attached from the less hindered convex face, which secured the correct configuration at C10.
Ensuing intramolecular aldol addition of diketone 15 proceeded employing KHMDS to form the D ring,
leading to the pentacyclic product 16 in 85% yield. After temporary masking of the C16 carbonyl group in
16 as its corresponding dimethyl acetal using TiCl4/MeOH, the resultant ester was converted into aldehyde
17 via a reduction–oxidation sequence.”

Các câu hỏi về tổng quan:

1. Vẽ các sản phẩm trung gian sau bước b), d), e) và i).
2. Vẽ các sản phẩm trung gian sau bước j), n), q) và r).
3. Giải thích chọn lọc lập thể cho bước g).
4. Đề nghị cơ chế hoàn chỉnh cho phản ứng từ 7 sang 6 (bước l).
5. Đề nghị cơ chế hoàn chỉnh cho phản ứng từ 6 sang 5 (bước m).

Hãy viết một đoạn văn ngắn phản biện đề tài này.

Gợi ý: Bàn về phản ứng chìa khóa tạo khung phân tử, chọn lọc lập thể của các phản ứng oxid hóa khử,…
 Thử thách 3: Tổng hợp toàn phần (-)-Retigeranic acid A

Đoạn trích trong báo khoa học và chuỗi phản ứng:

“The total synthesis of (−)-retigeranic acid A (3) commenced with decagram-scale construction of
aldehyde 22 bearing the trans-hydrindane framework (AB rings). A Henry condensation of the
commercially available aldehyde 14 (98% ee) with EtNO2 followed by a one-pot Nef reaction in the
presence of DABCO and O2 proceeded smoothly to afford enone 15 in 82% yield. Ensuing chemo-selective
Wittig olefination was achieved on the more reactive C15-ketone at −20 °C and produced a homologated
keto-aldehyde upon acid hydrolysis. Through modification of the protocol developed by Stork and Fallis,
a Zr(n-PrO)4-mediated intramolecular Michael/aldol cyclization sequence forged two consecutive
stereocenters at C14 and C15, delivering the trans-hydrindenone 16 along with its C14-epimer and C14,15-
diepimer as an inseparable 25:1:1 mixture in 60% combined yield over two steps. After conversion to α-
iodoenone, a palladium-catalyzed cross coupling with isopropenylmagnesium bromide under Negishi
conditions provided keto-diene 18 in 79% yield over two steps. By treatment with ICH2Cl and
TMSCH2Li·LiBr to initiate a cascade epoxidation/Meinwald rearrangement transformation, aldehyde 20
was exclusively detected presumably due to minimization of steric repulsions between the C22-hydroxyl
and the pseudo-axial C23-Me group on top face during the hydride migration process (via conformer 19).
Fortunately, a spontaneous epimerization at C12 was observed upon quenching the reaction with aq.
NH4Cl, leading to the formation of 21 in 65% yield. A Van Leusen homologation of 21 in the presence of
TosMIC and t-BuOK took place successfully, which was followed by DIBAL-H reduction to furnish 22 in 62%
yield.”
“The 1,2-addition of an organolithium reagent derived from bromophenol 23 to 22 afforded vinylphenol
24 in 67% yield. Subsequent ODI-[5 + 2] cascade reaction casted pentacycle 7 via the intermediacy of 25
as a sole isomer in 53% yield on a gram scale. In comparison, two congeners bearing a C2α-isopropenyl
group merely gave the corresponding adducts with opposite stereochemistry at C3, which supported our
hypothesis that the preinstallation of Δ1,2-alkene was crucial to the diastereoselectivity of this reaction.
Gratifyingly, the reductive skeletal rearrangement of 7 occurred uneventfully and directly provided
alcohol 26 in 70% yield by exposure to SmI2 (7.0 equiv) and quenching with H2O. Of note, up to five
transformations were involved in this cascade process. The C5-alcohol of 26 was found capable of
directing a regio- and stereoselective hydrogenation on the Δ7,8-alkene in the presence of Crabtree’s
catalyst, which itself was then eliminated under Chugaev conditions, affording 27 in 81% yield. The newly
formed Δ4,5-alkene on the C ring was saturated through further hydrogenation, accompanied by
concomitant isomerization of the C1–C2 double bond to the C2, C12 positions. Upon oxidation with PCC,
28 was obtained in 83% yield. By UV irradiation of the corresponding diazo precursor in methanol to
induce a Wolff ring contraction, methyl ester 30 was formed as a single diastereomer in 56% yield,
alongside a carbene O–H insertion to deliver 29 as a minor component (6% yield).

Having secured 30 in sufficient quantities (>250 mg prepared within two batches), we focused on its
conversion to methyl retigeranate. Disappointingly, the direct alkene isomerization of 30 met with failures
toward various acidic and basic conditions. On the other hand, an array of homogeneous (e.g., Crabtree’s
and Wilkinson’s cat.) and heterogeneous (Pd/C, Adam’s cat., Ir-black, etc.) hydrogenation trials also
resulted in complete recovery of the starting material.

Inspired by the pioneering work from Wender and co-workers, a regioselective hydrogenation of diene-
ester 31 was executed. To this end, a dibromination/elimination sequence was utilized by subjection of
30 to PyHBr3 and DBU, affording 31 in 58% yield. However, under Wender’s conditions for a diene-amide
derivative [Pd/C, H2 (400 psi), benzene, 25 °C, 14 days], only a trace amount of methyl retigeranate
together with its C2-epimer were detected (ca. 1.2:1, < 10% combined yield). The low efficiency of this
reaction prompted us to pursue alternative solutions. After extensive optimization, we found that a MHAT
reduction of 31 proceeded smoothly to furnish a 4.4:1 mixture of (−)-retigeranic acid A (3) and C2-epi-3 in
54% combined yield after saponification workup. The use of Ph(i-PrO) SiH2 discovered by Shenvi and co-
workers was critical to the reaction’s success. In comparison, other reductants such as NaBH4, Et3SiH,
PhSiH3, and TMDSO exclusively converted 31 back to 30. Both synthetic (−)-3 and 32 exhibited identical
NMR spectroscopic data to those reported, thus confirming the completion of total synthesis. Notably,
we have obtained the 13C NMR spectroscopic data of (−)-3 for the first time, which was absent in previous
isolation and synthetic works for unknown reasons.”

Các câu hỏi về tổng quan:

1. Đề nghị cơ chế hoàn chỉnh cho phản ứng từ 15 sang 16 (bước b và c).
2. Đề nghị cơ chế hoàn chỉnh cho phản ứng từ 24 sang 7 (bước i).
3. Đề nghị cơ chế hoàn chỉnh cho phản ứng từ 7 sang 26 (bước j).
4. Đề nghị cơ chế hoàn chỉnh cho phản ứng từ 28 sang 30 (bước m, lưu ý 29 là sản phẩm phụ của quá
trình này).
5. Tại sao phản ứng đồng phân hóa 30 để tạo thành 32 thất bại dù nhóm nghiên cứu đã cố gắng thử rất
nhiều điều kiện?

Hãy viết một đoạn văn ngắn phản biện đề tài này.