Cascade reactions on selected unsaturated diols: A mechanistic rationale

~

r."ah.dro1l UlltrS. Vol. 36. No. 48.

Pergamon

pp. 8783·8786. 1995

ElsevIer SCIence LId Printed in Oreal Britain

0040-4039195 59.50+0.00

0040-4039(95)01875-1

Cascade Reactions On Selected Unsaturated Diols: A Mechanistic Rationale S. Arseniyadis·, L. Toupet§, D. V. Yashunsky, Q. Wang and P. Potier lnstitut de Chimie des Substances Naturelles. CNRS. F-91198 Gir-sur- Yvette (France) § URA au CNRS. Universite de Rennes I. F-35042 (France)

Abstract: A mechanistic rationale for the oxidative rearrangements of unsaturated diols 1 and 2 leading to the tetrasubstituted cyclohexane and cycloheptane derivatives 3 and 4 is presented.

Recent reports from this laboratory disclosed that efficient cascade transformations can be effected by treatment of the unsaturated diols 1 and 2. obtained from Hajos-Parrish and Wieland-Miescher ketones by standard transformations. 1 with a single reagent. lead tetraacetate (LT A). in one pot at room temperature. 2 The cascade proceeded without any side reaction to give the desired 3 and 4. thus offering a new and easy access to tetrasubstituted six and seven membered rings with four contiguous substituents in their optically pure form (both antipodes available) which are of wide utility in natural product synthesis. Subjection of diols 1 and 2 to LTA mediated fragmentation in CH 3CN afforded 3 3 (14 h. 82%,95% average yield per job) and 4" (50 h. 50% • 84% average yield per job) respective!y.5 Thus. compounds S. a highly functionalized homochiral taxoid Coring intermediate offering C-2 and ColO linking possibilities. and 7 (Y =CHMe2' or CHPh) were obtained in only three steps starting from the corresponding diols. While no special efforts were taken to optimize these reactions. we have undenaken a thorough investigation in an effort to clarify the mechanism as well as to test the

HnS

H

effectiveness and scope of this synthetically useful transformation. We first examined the effect of BU

HO

~

1

S

~BU ',6

19

,

AcO Ac

ClIp

H~U

H~ 2

6

3

W BU

Ac

7

AcO 0

~u

HO~

o'

Pb(OAc)4

tDu

4

H~

(i

~ HOS?! o 8

changing several reaction parameters. Increasing the reaction temperature resulted in a decrease in chemical yield in comparison with reactions run at room temperature. Using a tenfold excess of LTA gave no evidence of significant alteration in the product composition and reaction rate. whereas using only one equivalent stopped 8783

8784

the cascade after the second job, leading to the tricyclic enol ethers 10 (not isolable) and 15. Changing the solvent to benzene showed only marginal effects on the reaction rate and chemical yield (slightly slower reactions and comparable yield). While the precise mechanistic details have yet to be rigorously established, most of them can reasonably be rationalized by Scheme 1. Thus, tricyclic product 3 involves the formation of the intermediate dialdehyde 9 (oxidative fragmentation, job-I) that collapses to give 10 via either an intramolecular hetero-Diels• Alder or its ionic version, an intramolecular Michael type addition (job-2), setting the conditions for the next step: an electrophilic attack of the metal6 to the electron rich olefin (job-3) leading to 11. The strain associated with this ring system then favors a ring expansion through 11 with concomitant loss of a Pb(OAch unit and acylation at C-2 (for sake of comparison the taxoid numbering is retained in the Hajos-Parrish series). The thermodynamically favourable valence change 7 and the ability of Pb4+ to act as a multijob reagent, such as an oxidizing agent (job-I), as a Lewis acid (job-3 and probably job-2, catalyzing the IMDA) and the high polarizability of the Pb-C bond associated with its low dissociation energy account well for the proposed mechanism of the cascade transformations.

Job-l ~

~/'~u

~

or

9Z

~~ ~ t u

r(~

\:

9Z

H4

10

I~u

(~

~ 12

'0-.-

l)Pb(OAC)3 Job-3 I ~ -AcO- OAc~

u

d~c

BU

H

t OAc

~Pb(OAC>2 o

11

Scheme I Separate control experiments have been carried out to ascertain whether the not isolable 10 might be an intermediate in the formation of ring-enlarged product 3. Treatment of 1 with only one equivalent of LTA led to the equilibrium mixture 9Z+10 (nearly I: I). characterized as a mixture. This mixture can be stored for weeks without any detectable change, Resubmission to the cascade conditions. with two equiv. of LTA. leads to 3. thus making it reasonable to conclude that 10 is formed as an intermediate. The same equilibrium mixture was also obtained by treatment of 1 with sodium pcriodate in THF-H20 for 5 min, which on prolonged reaction time (2 h) afforded the aldehyde 9E. The latter does not give furthcr cascade-type transformations when treated with excess LTA.

Pb(OAc)4 2,~ "'IUIV.

0ji?BU

-/1--.&

Nal04 ......1 - - -

3 ...

CH3CN.rl

0

9E

THP·H20 2h.rl.

Pb(OAc)4 [~tBU

---.~ I "'I wv. CH3CN,r.l.

@tBJPb(OAC)4 •

~

.&

9Z

•

25

0"

-

.

eqwv.

3

10

Insofar as formation of the bicyclo[2.2.2]octanone 6 (m.p. 94-5°C (pentane); [1l]D +55(c 1.3); IIREII\IS calcd for C13H2203 226.1569, found 226.1570) upon basic hydrolysis is concerned. a saponilication leading to 14 through a decarbonylation on 13 and subsequent aldol condcnsation as portrayed in Scheme 2. seems to be a reasonable mechanistic pathway.

8785

3

KzC03

M.OH.HzO~ r.L

[

.-.,~U

~ ---+ @: "1 ~

B"')H

6H\

O~U ~ H

13

04?DU

---+

0

-..

O~~ -

6

~ -

14

Scheme 2 Insofar as the synthesis of seven membered ring systems8 is concerned. different reaction conditions. as with 1. were used to monitor the formation of individual products from 2. In designing this synthesis we anticipated that the same mechanistic course would operate to give the cation 16. The results are consistent with the sequence of events proposed in Scheme 1 (job-l through job-4) until 16. afterwards they diverge. Resonance stabilization at this point would lead to bridgehead double bonds on 12 and 16. Due to the relative strain energies of these putative" Anti-Bredt" 9 cations 12 and 16. we can assume that one of these ring systems (the former) could not accomodate a bridgehead double bond. From this point on. the favorable energy features associated with the resonance stabilization of cations and the introduction of an sp2 center in the seven-membered ring (thermodynamic stability of the product) dictates the specific reaction outcome. Thus, acetate attack on the tertiary carbonium ion 12 leads to a strain-free six-membered ring with the bridgehead acetate 3 being the only product formed. The skeletal rearrangement proposed for intermediate 16 represents an alternative mode of breakdown which is preferred because it releases strain associated with the eclipsing and transannular interactions. The latter could evolve in two ways to yield a ring-expanded product: either by direct attack of the acyl ion yielding an sp3 center in the seven-membered ring or by forming first cation 17 and subsequent acyl ion attack. In the case of the ion 16 the direct acetate attack would involve severe steric interactions between the incoming acetate moiety and the neighbouring groups. thus the postulated intermediate of type 17 can rationalize the addition of the acetate residue at C-2 (numbering is arbitrary). The driving force for the above transformation could be attributed to the enhanced stability of the seven-membered ring due to the relief of non-bonded interactions accompanying the transformation of a tetrahedral ring atom into a trigonal one. Treaunent of diol 2 (3.33 mmol) with Pb(OAc)4 (6.54 mmol) for 3 h at room temperature. gave the stable and easily isolable tricyclic enol ether 15 (91% yield after Si02 flash chromatography. heptane-ether 1:1; [a]D -13. c 1.0); m.p. 46-48 0 C. pentane; HREIMS: calcd for ClSH2403 252.1725. found 252.1709). Treatment of 2 or resubmission of 15 to cascade conditions for two days afforded 4 in 50% yield along with 15 (30%). We attribute the lower yields obtained through this cascade to the added constraints imposed by the seven membered ring system.

W

Finally. the transformation of 4 to 8 may be explained by the same mechanism as for 3 to 6.

Q5

BU

"

6

0,'

-

15

Pb(OAc~ ~_

0I3CN 2h

Pb(OAc)4

2

~

H

---1.~I . ( ) . CH)CN • , 48b

BU

OAc

+

16

u

AcO-

'\ +t

Ac I

09

-. ], 4

:

H

6Ac

11

•

6 7

--.. Ac6 H

'

4

Scheme 3 In conclusion. the studies presented above have resulted in the development of a new cascade-type methodology for the construction of synthetically interesting ring systems. The mild reaction conditions together

8786

with the simple experimental and the absence of any detectable side products constitute the most outstanding feature of this new cascade methodology. Obviously. many extensions of this work can be envisaged and we are currently studying a number of possibilities for the design of several cyclic and bicyclic frameworks starting from the appropriately substituted unsaturated diols. 10

References and notes 1.

2. 3.

4.

5. 6.

7.

8. 9. 10.

Arseniyadis. S.; Rodriguez. R.; Munoz Dorado. M.; Brondi Alves. R.; Ouazzani. J. and Ourisson. a. Tetrahedron 1994, 50. 8399-8426. Arseniyadis. S.; Yashunsky. D.V.; Brondi Alves. R; Wang, Q.; Toromanoff. E.; Toupet. L. and Potier. P. Tetrahedron Lett. 1994.35,99-102; Arseniyadis, S.; Brondi Alves, R; Yashunsky. D.V.; Wang, Q. and Potier, P. Tetrahedron Lett. 1995.36. 1027-1030. 3: m.p. 103-4°C (pentane-ether); [a]D -33 (c 0.9); IR: (CHCI3) v 2973. 2933, 1738.1390. 1368, 1269. 1256, 1245. ll92. ll40. 1098. 1080.976,951,937,917 cm- I ; lU·NMR (400 MHz, CDCh) S 1.21 (s. 9 H), 1.29 (s. 3 H, Me-8), 1.58 - 1.77 (m. 2 H. H-5aeq and H-6~eq), 1.64 (dd. J=1.6, 14.1, H-9~). 1.77 (dd. tH. J=2.6, 14.1, H9a),1.88 (ddt. 1 H, J = 2.4, 4.8, 13.2, H-6aax), 2.10 and 2.11 (s, 6 H. M.e.C=O), 2.71 (dt, 1 H. J = 4.8, 13.0, H-5~ax), 3.14 (d, I H, J=0.8, H-3), 3.29 (t, 1 H, J= 2.4, H-7). 5.32 (t. I H, J= 1.6. H-IO), 6.42 (d, 1 H, J= 1.1, H-2); 13C·NMR (75 MHz, CDCI3) S 21.2 and 22.5 (M,e.C=O). 25.4 (C-6). 25.7 (Me-8). 28.4 (C-5), 28.9 (t-Bu). 36.1 (Cq-8). 36.7 (C-3), 39.6 (C-9). 72.7 (C-7). 73.5 (Cq-OtBu), 90.7 (C-2). 92.6 (C-IO), 104.2 (C-4). 169.2 and 169.6 (MeC:.Q); MSCI: mil. 297 (99), 57 (100). 4: m.p. 135-6°C (pentane); [a]D -39 (c 1.3); IR: (CHCI3) v 3022,2978.2936. 1752, 1716. 1391. 1366. 1230. 1217. 1189. ll73. 1109. 1071. 1049, 1021.994.947.926 cm- 1; IH-NMR (400 MHz. CDCI3) S 1.15 (s. 9 H). 1.31 (s. 3 H, Me-ll). 1.62 (m. 1 H, H-8a), 1.75 (m, 1 H, H-9a). 1.78 (dd. 1 H, J= 2.1. 14.6. H-l~). 1.92 (dd. 1 H. J= 4.3. 14.6. H-la), 1.93 (m. 1 H, H-8~). 2.00 (dq. 1 H, J= 2.6. 12.1. H-9~). 2.08 and 2.11 (s,6 H. OAc), 2.41 - 2.54 (m, 2 H. J= 7.1. 11.6, H-7,7'), 2.93 (d, 1 H. J= 3.4. H-5). 3.05 (d, I H. J= 8.9. H-IO), 6.34 (d. 1 H, J= 3.4. H-4). 6.40 (dd, 1 H. J= 2.1. 4.2, H-2); 13C·NMR (75 MHz. CDCl3) S 20.5 (Me-ll). 20.8 and 21.0 (Ac). 22.5 (C-8). 28.7 (t-Bu), 30.6 (C-9). 35.2 (C-l). 37.4 (C-ll). 45.3 (C-7). 53.8 (C-5), 73.7 (Cq-tBu), 79.4 (C-IO), 88.4 (C-4), 92.1 (C-2). 168.7 and 168.9 (Ac). 208.8 (C-6); MSCI: mil. 311 [(M+H)-AcOH] (99). 195 (27), 57 (loo). Even though the waste to product ratio (E) remains convenient, the use of a heavy metal with a high "unfriendliness quotient" (Q) does not help for the "greening" of organic synthesis; Sheldon. R.A. Chemtech 1994, 38-47. There is substantial precedent for the electrophilic attack of an olefin by metals which react as typical electrophiles; for T13+ : McKillop. A. Pure Appl.Chem. 1975.43,463-479. for H g2+ : Larock RC. Tetrahedron. 1982,38. 1713-1754; Arseniyadis, S; 001'6, 1. Tetrahedron Lett. 1983,24,3997-4000; for Ag+: Arseniyadis. S; Sartoretti. J. Tetrahedron Lett. 1985,26, 729-732; for Pb4+ : Levisalles, J.; Molimard. J. Bull.Soc.Chim.Fr. 1971. 2037-2047; Ephritikhine. M; Levisalles, 1. idem, 1975, 33~­ 344; ; Rubottom, a.M. Oxidation in Organic Chemistry, Trahanovsky, Part D. Chapter I, AcademiC Press, Inc. 1982. For the oxidation-reduction potential of Pb4+/Pb 2+, Latimer states a value of 1.7V: Latimer, W.M. "The oxidation states of the elements and their potentials in aqueous solutions", Prentice Hall. N. Y., 1952. For synthetic routes to enantiomerically pure cycloheptanones see: Batty, D.; Crich, D. Tetrahedron Lett. 1992.33, 875-878; for racemic cycloheptenones see: Pak, C.S.; Kim, S.K. J.Org.Chem. 1990,55, 1954-1957; Demole, E.; Enggist. P.; Borer. C. Helv.Chim.Acta 1971.54, 1845-1864. For the original definition of the Bredt's rule see: Bredt. J. Ann. Chem. 1924,437. 1-13; for a systematic investigation of the limits of the Bredt's rule see: Prelog, V. J.Chem.Soc. 1950,420-428; for a more recent review see: Shea. KJ. Tetrahedron 1980.36.1683-1715. Complete 1Hand 13C-NMR data were obtained for each compound synthesized; structure of 3 was further corroborated crystallographically. Optical rotations were measured in chloroform.

(Received in France 27 July 1995; accepted 29 September 1995)