Kanai Lab Literature Seminar (B4 Part)

Feb. 9th 2011
Y-F, Wang

Total Synthesis of (+)-Peloruside A

Total synthesis:
E.N. Jacobsen et al.ACIE, 2010, 49, 6147-50

1a: (+)- peloruside A

Other total synthesis route:
J.K. De Brabander et al. ACIE, 2003, 42, 1648-52((-)-peloruside)
D.A. Evans et al. JACS, 2009, 131, 3840-41
T.R. Hoye et al. ACIE, 2010, 49, 6151-55

Isolation: from Mycale hentscheli (a marine sponge of the Pelorus Sound in New Zealand),and it also produces two other useful secondary metabolites mycalamide A (antiviral&antitumor),pateamine (imminosuppression).
(L.M. West, P.T. Northcote, J. Org. Chem. 2000, 65, 445-449)
Stuctural feature:
Relative stereochemistry determined by Northcote et al.(JOC, 2000, 65, 445-449);
absolute one was determined by J.K De Brabander et al.(ACIE, 2003, 42, 1648-52).
Polyoxygenated 16-membered macrolide containing 10 stereogenic centres. Becides above, highly
substituded pyranose ring, Z-configured trisubstituded olefin and sterically crowded C8-C11 unit
would also become challenges in synthesis.
Peloruside A and B is differentiated in the methylation at C15.
Biological activity:
A potent antitumor agent with microtubule-stabilizing activity, induces cell-cycle arrest in the G2-M
phase acting in the similar manner as paclitaxel(Taxol), but in different binding site. The C24 primaryalchohol and pyranose ring are reported to be essential in peloruside's bioactivity.
(J.H. Miller et al. Cancer Res. 2002, 62, 3356-60; J.F. Diaz et al. ChemBioChem. 2010, 11, 1669-78)

Contents:
1. Jacobsen's Total Synthesis of (+)-Peloruside
1-1 Retrosynthetic Analysis
1-2 Jacobsen-Katsuki Epoxidation
1-3 Asymmetric Ring-Opening (ARO) of Epoxide
1-4 Jacobsenn Hydrolytic Kinetic Resolution
1-5 Asymmetric Hetero-DIels-Alder Reaction
Catalyzed by Metal-Salen Complexes
1-6 Total synthesis route

2. Tppic: Construction of 1,3-diol Moiety
via "inconventional" way
2-1 Oxygenation of Vinylclopropanes
2-2 Carbenoid insertion to alchohol moiety-C-H bond
2-3 Direct C-C Cross-Couping
2-4 Selective C-H Oxidation
2-5 Perspective

1.Retrosynthetic analysis

macrolactonization

reductive aldol reaction

allylation of aldehydering opening &chain elongation

asymmetric
Hetero Diels-Alderreaction

Key strategy:
1. Construction of three different enantioenriched epoxides (8,9 and 11) by using catalytic asymmetricepoxidation and series of asymmetric ring opening (ARO) reaction of nonoptical epoxide (e.g. Asymmetric Payne rearrangement, Hydrolytic kinetic resolution)

HKR

O

O
OTBS

8
O

Asymmetric epoxidation
Me

Me

9
O
HO

intramol. ARO
OH

O
OTBS
OMOM

11

2. Asymmetric hetero DIels-Alder reaction in synthesizing multisubstituded pyranose ring.
(In this route, by using tridentate chromium(III)-salen catalyst)

2. Jacobsen-Katsuki Epoxidation
Initial report~Focus on Metal-Salen Complexes (I)~(1) E.N. Jacobsen et al. J. Am. Chem. Soc. 1990, 112, 2801-03;

ORTEP view of the cationof (S,S)-1-[acetone]2

Catalytically Active Spiecies in Jacobsen-Katsuki Epoxidation
Remembering a well-known and ubiquitous oxo-transfer model in living body--- cytochrome P-450,
which possesses an iron-porphyrin active site wherein the molecular oxygen is activated as a formof iron-oxo species and then transfered to substrate.

Catalytic cycle of cytochrome P-450
Groves J.T. et al. Adv. Inorg.
Biochem. 1979, 119-45

Proposal: Formation of Mn-oxo complexes 2 in the Jacobsen-Katsuki epoxidation

Though no direct observation of MnV-oxo complex was achieved, the similar CrV-oxo model was
unambiguously clarified by Kochi et al. (JACS, 1985,107, 7606-17) and the direct indentification of MnVoxo complex with electrospray tandem mass spectrometry was achieved by Plattner et al. (ACIE, 1997,
36, 1718-19)
Studies on enantioselectivity
From the result on fomer page, three structural features of the catalyst 2:(1) the presence of bulky tBu-groups to prevent substrate awayfrom the diimine bridge (approach c)(2) the dissymmetry of the diimine bridge, which defavors attackfrom the side syn to the phenyl group(3) the steric bulk of diimine's two phenyl groups disfavors attackfrom the other side of diimine bridge

approach a (favored)

approach c (disfavored)

approach b (disfavored)(2) E.N. Jacobsen et al. J.Am. Chem. Soc. 1991, 113, 7063-64

The possible reason for steric inversion:
In case of cat. 2~5, it is less hindered than 1 in the vincinityof the diimine bridge, and this arise competitive attack fromapproach d.
Further more, when changing Me on the Salen's benzen ring
into much bulkier t-Bu(cat 5), attack from approach a was blocked
thus approach d become dominant pathway.
Face selectivity may be attributed to the axial hydrogen's hinder
to the larger substituent.
NaClO

cat. 5

CH2Cl2O

* Two proposal for approach of olefins to the Mn-oxo salen complex 5
Jacobsen's proposal:
The bulky t-Bu groups blocks all the possible access direction
except the diimine bridge side (b). At the same time, the axial
hydrogen atom on diimine bridge directed away the larger sub-stituent on the olefin.
Katsuki's proposal:
The direction of olefins approach was determined not only bysteric pulsions but the repulsive - interactions between the benzene ring of salen ligand and the unsaturated olefinic substituent.
6

Katsuki et al. Chem. Lett. 1995, 339
entry

substrate12''

catalyst

solventoxidanttemp.

yield(%)% ee

Confign.

6

CH2Cl2

NaOCl

0oC

78

91

1R,2S

7

78

97

1R,2S

6

75

91

3R,4S

7

70

97

3R,4S

7
3

Ph
4

''

Above was proofs that contradict Jacobsen's axial steric repulsion propasal by
Katsuki et al.. Since complex 7 bears axial methyl groups at C3'' and C6'' whichshould lead to opposite streostructure of products if Jacobsen's proposal was right.

Mechanistic Study of One Oxygen Atom Transfer from Mn-oxo Salen Complex to Olefins

Concerted path

Radical path

Manganaoxetane path

Although the factors controlling the enantiselectivity of Mn-salen comolexes are well understood,
the mechanism of oxygen transfer stage remains controversial.
From first experimental results, it was summarized that(a)alkyl-substituted alkenes proceeds though concerted path (A), as they only gave cis-product(b)conjugated alkenes proceeds in radical path (B),However, compare experiments with same substrate cis- -methylstyrene under different conditions,
it becomes clear that this conclusion is incorrect.

QAS

Extract from:
E.N. Jacobsen et al. JACS,1997, 109, 1798-1801;
E.N. Jacobsen et al. JACS,1994, 116, 6937-38;
T. Katsuki et al. J. Mol. Catal. 1996, 87-107

The epoxidation of vinylcyclopropanes provide a good indication for radical intermediates, as these "radical
clocks" undergo ring-opening at a rate of approximately1011 s-1.

Extract from:
E.N. Jacobsen et al. JOC, 1991, 56, 6497-6500
B. Akermark et al. ACIE, 1997, 36, 1723-25

To sum up above experimental results, it becomes clear that the diastereoselectivity are strongly dependent
on the oxidant, the catalyst and the additives.
Summary:
1. J-K epoxidation is one of the most efficient methods for asymmetric epoxidation of unfunctionalized olefins(complementary to Prilezhaev reaction (racemic), and Sharpless AE(allyl alchohol)).
2. High enantioselectivity can be achieved in cis-olefins, cyclic olefins, and conjugated olefins. However, terminal
olefins and trans-olefins are usually poor substrate (in contrast of Shi-epoxidation, which is efficient in trans-olefins
and tri-substitude olefins).

3. Asymmetric Ring-Opening (ARO) Reactions of Epoxides~Focus on Metal-Salen Complexes (II)~3-1 Asymmetric Ring-Opening (ARO) Reaction of Epoxide by Metal-Salen Catalyst
Initial Report

E.N. Jacobsen et al. J. Am. Chem. Soc. 1995, 117, 5897-98
E.N. Jacobsen et al. J. Org. Chem. 1996, 61, 7963-7966

Initial conception of ARO strategy
The groud state structure of epoxides coordinate to metal complex may share similar pattern as thetransition state of olefin's epoxidation by metal complex oxo transfer.

(A) Schematic representation of the side-on
approach model for olefin epoxidation by chiralsalen complexes
Preliminary screen of metal salen complexes for ARO of epoxide(B) Possible model of epoxide activation
to asymmetric ring-opening by similar
catalyst

Mechanism of ARO
Active catalyst in ARO of epoxide by TMSN3(active catalyst)
5E.N. Jacobsen et al. Acc. Chem. Res.
2000, 33, 421-31

Evidence:
1. Byproduct 5 is generated only in the initial stages and in yields propational to the amount of catalyst
employed.
2. The catalyst separated after 1st cycle reveals N-Cr in molar ratio of 5:1 and the absence of Cl atom,also shows strong IR absorbence at 2058 cm-1 which is consistent with Cr-N3 N=N stretch.
3. No measurable loss of activity and enantioselectivity occurs when recycled up to another 10 times.
In fact, 2-N3 serves as both a Lewis acid for epoxide activation and an N3-dilivery agent. And the actual active
catalyst is in form of (salen)Cr(N3)(epoxide).
Unusual rate expression
The reaction of HN3 with cyclopentene oxide in presence of catalystic 2-N3 obeys the following rate law:rate = k[2-N3]2[epoxide]-1[HN3]0
A second order dependence on 2-N3 is observed. Based on this rate expression, the mechanism of metal-salen catalyzed ARO of epoxidation is proposed as follow:

TMSN3
+ H2O

TMS2O

Studies on cooperative reactivity of metal-salen complexes in AROThis second-order dependence on the catalyst strongly implicating the possibility of its showing extra
coorpertive effect when designed as dimeric or polymeric form.
Two limiting geometries of metal-salen complex dimer can be envisioned, respectively as "head to head"and "head to tail".

E.N. Jacobsen et al. JACS, 1998, 120,10780-81

Designed as the "head to head" transition stategeometry. Accelerated rate of ARO wasobserved. Kinetic experiments by plots of kobs/[cat] vs [cat] (fighur in next page) showscomplex 7 catalyzed the ARO primaryly through a first-order pathway.

Results earned from complex 7 and 8 suggest:
1. Cooperative reactivity was in fact occuring within the dimeric complex
2. The placement of tether (the link part) was critical to enantioselectivity
3. The "head to head" arrangement was not optimal geometry

Redesign dimeric complexes (4a~4g)in order to allow intramolecular reaction with a greater rangeof transtion state.

5Considering a two-term rate equation involving both intra- and intermolecular components:
rate = kintra[cat] + kinter[cat]2

nonlinear effects in ARO of cyclopentene oxidewith TMSN3 catalyzed by 5 and 4d

4. Hydrolytic Kinetic Resolution (HKR) of Terminal Epoxide--- Practical Application of the AROGeneral and practical method for enantioselective synthesis of terminal epoxide is still unavailable(refer to Summary of J-K asymmetric epoxidation), thus kinetic resolution of terminal epoxide from its
inexpensively available racemic mixtures becomes a very attractive strategy.
The strategy of epoxide HKR:First finding connected to the establishment of HKR
E.N. Jacobsen et al. Tetrahedron Lett. 1997, 38, 773-76(1)

37%>95% ee(2)

47%50% ee13%>95% eeInitial report of metal-salen catalyzed epoxide HKR
E.N. Jacobsen et al. Science, 1997, 277, 936-38

krel = ln[(1- c)(1- ee)]/[(1- c)(1+ ee)], where ee is the enantiomeric excess of the epoxide and c is the fraction of epoxide
remaining in the final reaction mixture.

98.5% ee98% eeIn cases of HKR, polymeric matal-salen complexes also represent coorperative effect just as ARO

E.N. Jacobsen et al. JACS, 2001,
123, 2687-88

5. Asymmetric Hetero DIels-Alder Reactions of Carbonyl Compounds~Focus on Metal-Salen Complexes (III)~a. Danishefski's diene as enophile(1)

E.N. Jacobsen et al. JOC, 1998, 63, 403-05(2)

E.N. Jacobsen et al. OL, 2002, 4, 1795-98(3)

T. Katsuki et al. Tetrahedron, 57, 845-51(4)

A. Berkessel et al. JOC, 2006, 5029-35

(b) other type diene
(1)

4

5

E.N. Jocobsen et al. JOC, 1999, 38, 2398-99(2)

A. Umani-Ronchi et al. Chem. Commun. 2002, 919-27(3)

Q. Feng et al. JOC. 2006, 71, 4141-46
Summary:
After decades of studies, it has been proved to be effective in asymmetric imine-cyanation, conjugate addition,
carbenoid insertion besides mentioned reaction types above. Thus makes it one of the so-called "priviledged catalysts"*.
The first inspiration from heme-containing enzymes finally develops into salen's great hit, similarly shared manyother "priviledge catalysts" such as Bi-oxazoline(BOX) ligand which was inspired by vitamin B12, These all reminds
us nature could always provides "nutrients" in ligand design.
* Reviewed by:
E.N. Jacobsen et al. Science, 2003, 299, 1691-93

Total Synthesis of (+)-Peloruside A
Synthesis of Intermediate 15 and 16
mCPBA,
DCM, 0oC~ r.t.
OH

HO

74%

1. (S,S)-13(0.02 mol% Co)

O

OH

OH

HO

29

O

MeCN
r.t., 14h

12

OH

then
TBSCl, DMAP,
Et3N, CH2Cl2,-20oC, 3hOO3, CH2Cl2,
-78oC

OMe

H

OTBS
OMOM

MgBr
CuBr (10 mol%)
THF, -40oC, 2h

OMe
OTBS
OMOM

then PPh3,
r.t., 3h; 91%30

1598% ee14

MgBr
CuBr (10 mol%)
THF, -40oC, 2hthen HMPA,
Me2SO4, r.t.
48h; 73%

2. MOMCl,DIPEA,
toluene, 16h,
56% for 2 steps

O
OTBS
OMOM

then HMPA,
Me2SO4, r.t.
48h; 73%

11

O3, CH2Cl2,
-78oC

O

OMe

then PPh3, H
r.t., 3h; 91%

OTBS
16

Synthesis of intermediate 7

O
MeO
31

(4.4 eq)
MeO
t-BuLi (1.3 eq)
MeOOBn
THF, -78oC,
4h; 68%O

32

LHMDS (1.3 eq)
Ac2O (1.5 eq)
OBn
MeO
THF, -78oC
1.5h; 68%

OAc
OBn

10
Me

Me
Me

adam
N

O
Cr

O

Cl

17

Synthesis of intermediate 4

Pd/C, IPA,
H2 (200 psi)
pH 7 buffer
69%

~100%

MeO

H
N

Me

NaClO, TEMPO,
KBr, pH 7 buffer,
CH2Cl2, 0oC, 1.5h

HCl

AlMe3
toluene, -10oC
90 min; 85%
33
1. TBSOTf,
2,6- lutidine
CH2Cl2,-78oC, 2h

2.
MgBr

Me
o

THF, 0 C~ r.t, 5h
45% for 2 steps
TBSOTf,2,6-lutidine
CH2Cl2, -10oC
4h; 86%

Synthesis of intermediate 3
1. 22 (5.0 mol%)
NaClO,CH2Cl2
0oC, 6.5 h
Me24

2. 23 (0.5 mol%)
H2O, Et2O,
0C~ r.t, 24hOMey. 41% for 2 steps
50% ee after epoxidation;
98% ee after HKR

8
1. EtMgCl, THF, -78oC~r.t., 4h
2. TIPSCl, imid., DMF, r.t., 16h

O
BHO
40~50oC, 48 h

1.

2. Br2, CH2Cl2,-78oC, 10min

Me

Br

OTIPS

Me
34

3. TBAF, THF,
40oC, 2.5 h
MgO, Ph-CF3,
83oC, 24 h

N OBn
69% for 2 steps
Me OTf

Me

Br

OBn

Me
35

1. PMBBr,
NaH,DMFr.t., 2h
2. AcOH, H2O
THF, r.t., 16h
70% for 2 steps

3+

s-BuLi, THF,
Et2O, -78oC
then 16, THF,
-78C~r.t., 16h
64%

PMBO
Dess-Martin periodine

OMe O

Me

H

CH2Cl2, r.t., 4h
83%

Me
OBn
3

L-Selectrid,
THF, -78oC, 2h

4then -40oC, 2h

HF/pyridine, pyridine
THF, 0oC~ r.t., 2h3.

PhI(OAc)2, TEMPO
CH2Cl2, r.t.,16h; 74%

O

Cl

Cl

1. NaClO2, NaH2PO4
isoamylene, H2O, t-BuOH
2. DDQ, pH 7 buffer
CH2Cl2, 5h(+)- peloruside1

Pd/C, HCOOH,
AcOEt, MeOH,
r.t. 1h
1N HCl, THF, r.t., 16h
then
4N HCl, THF, r.t., 3.6h

Cl
Cl

DIPEA, THF, r.t.,16h; then DMAP,
toluene, 60oC, 48h;
52% for 3 steps

Topic: All Roads Lead to Rome------Approach to the Synthesis of 1,3-Diol Moiety via "inconventional" pathway
As seen in pelorudside, 1,3-diol moiety is one of the most common structural units in many natural products.

(antifungal, antibiotic)(antiviral, antitumor)

Erythromycin(antibiotic)

Tacrolimus (FK506)(immunosuppressant)Although the defination of "conventional" would be quite controversial, here I simply categorize thesemethodologies (vida infra) as "traditional":
1. Selective reduction of 1,3-hydroxyketones or 1,3-diketones
2. Alkyl/allylation of 1,3-hydroxyketone moieties (Keck reaction, Prins reaction etc.)
3. Aldol(+reduction)
4. Conjugate addition by O-nucleophile/reduction
5. Manipulation of allylic or homoallylic alchohol (including addition of O-nucleophiles andiodocarbonation etc.)

Above all are some "traditional" way for synthesizing 1,3-diol moieties. All of them are well develpoed andhave been widely utilized. However, nevertheless the traditional methods have achieved great efficiency
and mature system, methods for oxidative approach or direct convertion from C-H bond are still limited.
Here I would like to introduce some thus "inconventional " method for constructing 1,3-diol moiety.

1. Oxygenation of Vinylcyclopropanes
Strategy:

The idea was inspired by the biosynthesis route of prostaglandin family:
O2

steps

COX

PGD2
PGE2
PDF2a
PDH2 etc.

(PGG2)

Report:K.S. Feldman, Synlett. 1995, 217-225
RO2
Ph2X2, AIBN/hv

O O
R(X= S or Se)

Cons:
Pros:
1. Can induce two oxygen atom for diol in single step.
1. Not easy to control (low dr. and ee)
2. DIrectly using molecular O2 as oxidant
2. Need reductive procesure
3. Initiator of S or Se compound is needed
3. Also promising in direct oxidizing poly-unsaturated moiety

Mechanistic study
R

O2

O O

Ph2X2, AIBN/hv

R

Cyclization of 5-hexenylperoxy
radical 19 is speed regulation step

Steric effect of substituents in syn/anti selectivity

71 syn69
boat-like form

chair-like form

72 anti70

1. Chair-like conformation and an equatorial substituent R at C(3) provides the lowest energy pathway
in most cases, which makes syn-form 71 as major product.
2. As increasing size of vinyl substituent R only had onlymodest stereoselectivity(26f-h) but reversionof sterwochemical preference occured(26f,i), these result indicates 68 is main route attribute to anti-form 72.

Electronic effect2. Carbene insertion to alchohol moiety -C-H bondStrategy
R1

OR3
R

OR3

R2

R1

R

H

R2

Report

H.L. Davies et al. OL, 1999, 1, 383-85

Ar

R2
N2

TBSO

MeO2C

(R1or/and R2 contain -O moiety)

Rh2(R-DOSP)4(1.0 mol%)R1

hexane, 23oC

Ar
R1

MeO2C

OTBS R2

entry

Ar

R1

R2

yield, %

de, %

ee, %

1*

p-ClPh

H

Et

48

76

-

2*

Me

Me

44

70

-

3*

Me

H

72

96

-

4

Me

H

72

96

80

5

Ph

H

70

97

85

6

CH=CH2

H

71

98

74

7

H

H

35

98

90

H

H

52

>94

92

8

Ph

red.

Ar
R1
OH OTBS R2* Using racemic catalyst

Mechanistic Study

Catalytic cycle of metallo-carbenoid insertion to C-H bondDoyle et al. Chem. Rev. 2010, 704-24

EDG/EWG co-substituted carbenoid gains unique properties:
1. Undesired carben dimerization pathway is significantly
reduced.
2. Selectivity of intermolecular C-H insertions is increased.
Reviewed by:
H.M. Davies et al. Nature, 2006, 451, 417-424

The large group(L) projects upward from cat.
The small group(S) points toward cabenoid andthe middle group(M) projects away from carbenoid.

However, the substition type of the allyl substrate influence the result of this reaction significantly.
The major side reaction is cyclopropanation.

19%

35%

When allyl acetate was used instead of silyl-ether, cyclopropanation became exclusive reaction.

y. 75%
Also, when 2-methylpropenyl silyl ether was used, cyclopropantion proceeded without C-H insertion product.

y. 54%
These results indicate :(1) Electron rich site proceeds insertion easily.Carbenoid prone to proceed insertion to C-H bondadjacent to EDG rather than EWG.
+

TBSO

N2

CO2Me Rh2(S-DOSHP)4
AcO
50oC
p-BrPhp-BrPhy. 92%>94% de,72% eeCO2Me
OTBS
H.M. Davies et al. JOC, 2003, 68, 6126-32(2) The steric factor influence carbenoid C-H insertion significantly.
OAc

Report 2

H.M. Davies et al. OL, 2, 4153-56
Ph
R1

HO

OH

d

Si(O-iPr)4 CH3,CH3

i-Pr

10

-

68

Ph
HO
OH

y. 32%
80% de97% eeThe mechanism of this reaction is supposed to be similar to the former one.

Summary:
Pros:
1. Carbenoud insertion one of the limited methods that can achieve high regioselectivity and enantioselectivity
in C-H activation by now.
2. This method provides an alternative to tradittional pathways.
Cons:
1. The yield is moderate in most case and always have side reaction.
2. Substrate scope is still quite limited. And direct insertion between two alchohol would be hard to be achieved,
as insertion direct O-H is highly competitive.

+1

y. 86% 1:2= 6:1
86% ee2
H.M. Davies et al. JACS, 2010, 132, 396-401

3. Direct C-C Cross-Coupling
Coupling of Alchohols at
Report:position with Aldehyde

Y-Q. Tu et al. Adv. Synth. Catal. 2008, 350,2189-93

So far, this is the only report which achieved this type of reaction. However, substrate of this reaction
was limited to t-BuOH only. When switch to other kinds of alchohol, a competing path which generate
THP skeleton.

alchoholaldehyde

productyield(%)
72

1a
1a

54

65

2a

63

2a

37

a. General conditions: 2 (1.0 mmol), 1 (2.5mmol), RhCl(PPh3)3 (2 mmol%),
CsCO3 (2 mmol%), BF3-Et2O (1.5 mmol) intoluene for 3-12h.
b. The dr of 4a is 3:2, and for 4b-4e only
one diastereomeric form was isolated.
c. Isolated yield based on the aldehyde 2
used.

Mechanism proposed by author:
Author proposed a pathway that includes dehydrationand LA-activated/Rh catalyzed Prins-type reaction.
Though the detailed reaction mechanism is still unclear,
the fact that either RhCl(PPh3)3 or BF3-Et2O alone
could
not effectively promote this coupling reaction in parallel
experiments suggests co-work of LA and Rh-catalyst
is essential.
Summary:
Pros:
1. The only report that achieved direct coupling fromalchohol and aldehyde to form 1,3-diol up to now.
2. Protection free, easily achievable reaction condition.
Cons:
1. Very limited substrate scope
2. Yields are no more than moderate
3. Competitive pathway

4. Selective C-H Oxidation
Selective oxidation oriented by directing group
Report: P.S. Baran et al. JACS, 2008, 130, 7247-49

Scheme 1
General procesure (Take 17 as example)

17

StrategyOO
R1

cf. Hofmann-Loeffler-Freytag (HLF) Reation

NHR
R2

Main challenges in this new type of reaction

Usual transformation in HLF reaction
Hb vs Ha(A) Selective transfer of 1,6-hydrogen via relatively
unstable 7-memberd transition state

1,5-hydrogen transfer via 6-memberedtransition state

O vs N(B) Cyclization from carbonyl O atom (forming iminocabonate D)

Cyclization from N atom (forming cycliccarbamate)# Solution to challenge A --- Tuning the side chain on N atom
The side chain on carbamate N bears great influence on the reactivity of N-bromocarbamates
The more electron-withdrawing group it is, the higher the reactivity was obtained.

<

<

<

# Solution to challenge B --- Employing Ag2CO3 to promote cyclization to iminocarbonate
Summary:
Pros:
1. Provide an unprecedent way directly convert alchohols to 1,3-diols, also with relative high efficiency.
Previous synthesis: 4 steps, 12%
J.G. Rico et al. TL, 1984, 25, 5977-80(y. 70%, dr 8:1)

(More aplications of this method in total synthesis please refer to Dr. Yin's Lit-seminar handout)
2. Shows excellent regioselectivity among dierect C-H oxidation methods.
Oxidation prodduct

Oxidation prodduct

This method:
single regioisomer at Hc, 55%

This method:
single regioisomer at Hc, 42%

White catalyst(Fe-based):
Ha : Hb in 3:1, 42%, no Hd

White catalyst(Fe-based):
single regioisomer at Ha, 51%

Curci method(dioxirane):complex mixture, 91%

Curci method(dioxirane):complex mixture, 86%

Cons:
1. Only benzylic and tertiary C-H are oxidized in synthetically useful yields.
2. Olefins, free carboxylic acids, amines, amides, unprotected alchohols, and azides are not tolerated.

Other methods of 1,3-diol moiety construction via selective C-H oxidation via directing group
a.

O
O

H

CF3
Me

MeO

N
R2

R1
c.

HO
R1

O
OH

t-BuOH/H2O

Meb.

Oxone, NaHCO3
Na2-EDTA

N
R2

Me

O
CF3

y. 51%

M. Inoue et al. OL, 2009, 11, 3630

Me

Pd(OAc)2 (5 mol%)
PhI(OAc)2 (1.1 equiv.)

MeO

Ac2O:AcOH (1:1)
100oC

R1

Pd(OAc)2 (5 mol%)
PhI(OAc)2 (1~ 3 equiv.)

AcO

Ac2O:AcOH (1:1)
80 -100oC

R1

other 5 samplesN

y. 39%~86%

OAc
R2

N

8 samples

Sanford et al. JACS, 2004, 126, 9542

y. 33%~66%

OAc
R2

6 samples

Sanford et al. OL, 2010, 12, 532(More detail please refer to Dr. Yin's Lit-seminar handout)

Perspective of 1,3-Diol Moiety Induction via Selective C-H Activation(1) Direct Cross Dehydrogenative Coupling between Two Alchohols

OH
+
R1

R2

R3

OH
R4
R5

OH OH
R1
R4
R2
R5
R3

CDC

So far this type of reaction has not been achieved yet.
Main probable challenges in this reaction:
1.Selective activation of -C-H bond in one alchohol andC-H bond in another.

2. Reactivity control to prevent over oxidation and polymerization
Perspective:
1. This type of reaction is highly atom-economic
2. Would be very friendly to environment, when O2 is directly used as oxidant.
(2) Ultimate Oxidation ----- Selective Oxidation of C-H in "desired" site
The most ideal way to get 1,3-diol moiety would be selective oxidation to two-1,3-positioned sp3 C-H bonds,
without directing groups, only using O2 as oxidant, hopefully also with diastereao- and enantio-selectivities.
This idea sounds nearly "Mission Impossible", because even enzymes could not accomplish such task.
However, recent years some achievement in selective oxidation of unacticvted sp3 C-H brought light on
this "impossible" task.
(A)Predictable selective oxidation solely on the base of the electronic and stetic properties of C-H bond
was achieved.
----"A predictablely Selective Aliphatic C-H Oxidation Reaction for Complex Molecule Synthesis"
M.C. White et al. Science, 2007, 318, 783-87(Detail please refer to Dr. Yin's Lit-seminar handout)(B) Predicable and high chemo-,site-, and even diastereao-selective oxidation of methelene C-H bonds
was achieved.
----"Combined Effects on Selectivity in Fe-catalyzed Methylene Oxidation"
M.C. White et al. Science, 2010, 327, 783-87