a new strategy for efficient synthesis of medium and large ring

A New Strategy for Efficient Synthesis of Medium and Large

Ring Lactones without High Dilution or Slow Addition

Zhao, W.; Li, Z; Sun, J. J. Am. Chem. Soc. 2013 ASAP

Joshua Sacher

23 March 2013

O OR R'

OTIPSBF3•OEt2

2,4,6-collidine

CH2Cl2, 0 °C O O

R'n n+2+

Josh Sacher @ Wipf Group of 11 4/21/2013

Macrolactonization

Parenty, A.; Moreau, X.; Niel, G.; Campagne, J.-M. Chem. Rev. 2013, 113, PR1 Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95

O

O

16 O

O

O

OHHO OH

O

OO

O

NOH

OHOMe

14

Erythromycin A(antibiotic)

Exaltolide(perfume–musk) O

OO

NO

NO

N

O NH

CHO

OMe OAcO

HO

OMe

25

Mycacolide A

Direct lactonization: •  Activated acids (Carbodiimides, P-based, Yamaguchi, etc.) •  Carboxylate attack (Mitsunobu, Iodolactonization, etc.)

Indirect formation: •  RCM •  Olefination (Wittig, HWE, Julia) •  Others (ex: heterocycles, couplings)

96 Illuminati and Mandolini Accounts of Chemical Research

when they are forced close to each other. The magni- tudes of such strains have been evaluated by Allinger et al.” on the basis of force-field calculations. Strains (1) and (3) are especially severe for medium-ring cycloalkanes. Unfortunately, extensive strain energy data for ring compounds other than cycloalkanes are not available.

According to Ruzicka’s intuition,” the probability of the chain terminals coming close enough to each other for the reaction to occur should decrease as the chain gets longer. In terms of entropy, this implies negative AS* contributions owing to reduction of freedom of internal rotation around the single bonds of the molecular backbone when the disordered open-chain pre- cursor is converted into the ring-shaped transition state.

When studying an intramolecular reaction, we need a reference intermolecular reaction for comparison. Knowledge of the inherent reactivity of the reacting functional groups is of practical as well as theoretical significance. An obvious intermolecular model reaction is dimerization of the bifunctional substrate itself (eq 2). However, an experimentally more accessible model is the reaction between monofunctional chains (eq 3)

W Y f Y W k m z n u (3)

whose nonreacting moieties resemble the nonreacting chemical environment of the bifunctional chain that cyclizes. Model reactions involving low molecular weight monofunctional reactants have proved to be ~uitable.’~ Reaction 3 is more generally applicable than reaction 2 for purposes of comparing intra- to intermolecular reactivity. A specific example is our use of intermolecular model reaction 4b in our studies of lactone formation from w-bromoalkane-carboxylate ions (eq 4a).

/-

i_/ 1

+ b2in ’ = v Br- ‘Ja‘

Comparison is expressed by the klntrs/klnter ratio, which has units of moles per liter and is called effective molarity (EM). This name may be misleading because it suggests that the ratio klntra/kinter be taken as a physically real “effective concentration” of one chain end relative to the other, that is, that the fist-order rate constant for ring closure is the product of such “effective concentration” times the second-order rate constant for the reaction between the chain ends as if they were not connected by the intervening chain. That this is actually not the case is shown, for instance, by the finding7,8 that experimental EM values for rings 5 and 6 often exceed physically conceivable concentrations by several powers of ten. The EM concept has been discussed at length elsewhere14 and will be applied later on.

(11) N. L. Allinger, M. T. Tribble, M. A. Miller, and D. H. Wertz, J . Am. Chem. SOC., 93, 1637 (1971).

(12) (a) L. Ruzicka, W. Brugger, M. Pfeiffer, H. Shinz, and M. Stoll, Helu. Chim. Acta, 9,499 (1926); (b) L. Ruzicka, Chem. Ind. (London), 54, 2 (1935).

(13) C. Galli and L. Mandolini, J . Chem. Soc., Perkin. Trans. 2, 443 (1977).

(14) G. Illuminati, L. Mandolini, and B. Masci, J . Am. Chem. SOC., 99, 6308 (1977).

3 5 7 9 11 13 15 17 19 21 23

RING SIZE

Figure 1. Reactivity profile for lactone formation (eq 4a).

A useful corollary of the definition of effective molarity is that ring formation from a bifunctional substrate predominates over polymerization whenever the substrate concentration is markedly lower than the EM value. Since the EM values may strongly depend on ring size, the EM parameter enables prediction of the conditions under which a given ring can be synthesized free from competing polymerization rea~t i0ns. l~

The Reactivity Profile Lactone-Forming Reactions. The ease of ring

formation for lactones16-18 in 99% (v/v) aqueous Me2S0 (eq 4a) as a function of ring size is illustrated in Figure 1. On going from the three- to the five- membered lactone the rate constant increases by 5 powers of ten, but then the rate decreases rapidly to a nadir at the eight-membered ring; the overall decrease is a millionfold. The drop in rate in this region is ap- proximately 2 powers of 10 per added methylene group. The reactivity of lactone formation up to the eight- membered ring is somewhat lowered by the require- ments of the ring size to force the ester function into the cis conformation.16 Cyclization to the nine-membered ring is almost as slow as to the eight-membered, but from the ten-membered ring on the ease of ring closure increases again until it eventually levels off with the largest rings. The rate constants for the region of 13-23 lie well within a factor of 2. The substantial lack of sensitivity of rate to ring size in this region is in agreement with previous studies which were based on semiquantitative or preparative ~ o r k . ~ ? ~ Noteworthy

(15) C. Galli and L. Mandolini, Gazz. Chim. Ital., 105, 367 (1975). (16) C. Galli, G. Illuminati, and L. Mandolini, J . Am. Chem. Soc., 95,

8374 (1973). (17) C. Galli, G. Illuminati, L. Mandolini, and P. Tamborra, J. Am.

(18) L. Mandolini, J . Am. Chem. SOC., 100, 550 (1978). Chem. SOC., 99, 2591 (1977).


Previous Work

Zhao, W.; Wang, Z.; Sun, J. Angew. Chem. Int. Ed. 2012, 51, 6209

O

O

R

OTIPS 10 mol% HNTf2

CH2Cl2, 0.1 MO

RO

OTIPS

+

O

O

ROTIPS

O

R

O

OTIPS

prepared independently

H NTf2

O

RO

OH

SiR3

NTf2

O

RO

OH R3Si NTf2

[2+2] – HNTf2


Oxetene Fragmentation

O

O

O

O

O

O

OO

?


Real Examples

Rhee, J. U.; Krische, M. J. Org. Lett. 2005, 7, 2493 Arumugam, S.; Popik, V. V. J. Am. Chem. Soc. 2009, 131, 11892

Harding, C. E.; King, S. L. J. Org. Chem. 1992, 57, 883

TsNPh

O AgSbF6 (10%)

DCE (0.25 M)25 °C, 99%

TsN

O

PhTsN O

Ph

O

O

O

NMe3

OHh! (254 nm)

OEtO O O

MeCN/H2O89%

OHO

OBF3O O

BF3•OEt2Et2O, rt, 10 d

45%


Ynolates

Shindo, M. Tetrahedron, 2007, 63, 10 Shindo, M.; Mori, S. Synlett, 2008, 2231

R OR'

O

X

LDAR

XOR'

OLit-BuLi R

LiOR'

OLi

- LiOR'

OLi

R

X

RX

O

OR's- or t-BuLi

orLi/naphtalene

OLi

R

ON

H

Ph

R

n-BuLi ON

Li

Ph

R

OLi

R- PhCN

OLi

R

TIPS-OTf OTIPS

R


Ynol Ether Scope

R

OTIPSBF3•OEt2

2,4,6-collidine

CH2Cl2 (0.1 M)0 °C, 30 min

O OMe

O

OR

+

Entry12345678

yield91%85%77%89%84%64%62%58%

Rn-Bun-Oct

(CH2)3Phc-Prt-BuPh

(CH2)3OTIPS

C8H17

•  Optimized acetal, Lewis acid, additive •  Sterics not an issue •  Conjugation problematic •  R ≠ H (unstable ynol ether)


Proposed Mechanism

O OR O O N

collidine

RO BF3

BF3

R'

OTIPS

R'

O

RO BF2

F TIPS+

O R'

O LA

O

OR'

LA

OO

R'


Ketals: Selected Examples

O

OBnBnO OBn

BnO OAcNo Reaction

OO

n-Bu

H

70%

n-Bu

OTIPS

O

n-Bu

OR

ROTBSOBzN3

O-allylO-propargyl

yield75%56%52%65%63%

O OR'n

O

n-Bu

On+2BF3•OEt2, 2,4,6-col

CH2Cl2, 0 °C

8O

n-Bu

O O

n-Bu

O8

CH3

93% 77%

7O O O

(E)

O

n-Bu n-Bu

O9 10 18

86% 88%(1:1 E/Z)

87%

n-BuO


Extensions Iterative Ring Expansion:

n-Bu

OTIPS

BF3•OEt2, 2,4,6-colCH2Cl2, 0 °C

93%

On-Bu

OO OAc

1) H2, Pd/C

2) DIBAL; Ac2O, py68%

On-Bu

OAc

O O

n-BuOTIPS

OTIPS


65%

TIPSO

Acyclic Systems:

Ph On-C5H11

OAc n-Bu

OTIPS


86%

Phn-Bu

On-C5H11

O

O O

Ph

n-Bu

OTIPS


83% (5.7:1 E /Z)

Phn-Bu

O

O

OH


Conclusion

�  New methodology for forming medium- and large-ring lactones

�  Unprecedented ring expansion reaction manifold for oxetenes �  Normal reaction concentrations, no slow addition �  Iterative process possible to generate large rings from

inexpensive material

�  Must use substituted alkynes due to instability �  Potential problems with electronics of alkyne �  Limited use in complex systems to date.


a new strategy for efficient synthesis of medium and large ring

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