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11. TITLE (include Security Classification)

Enantioselective Ring Cl 2avage of men'o-Epoxides with -Halodiisopinocamipheylboranes

12. PERSONAL AUTHOR(S)N. N. Joshi, M. Srebnik and H. C. Brown

l3a. TYPE OF REPORT I13b. TIME COVERED 114. D)ATE OF REPORT (Year, Mon~th,ODay)1 PAe5E COUNT'* Technical J FROM TOI y17 'WR 2

16. SUPPLEMENTARY NOTATION

* 17. COSATI CODES 18 SUBJECT TERMS (Continue on reverse if necessary and Identify by block number)FIELD GROUP SUB-GROUP IIpc2BX, w,o.-mepoxides, encontioselective ring cleavage,

1 ,2-halohydrins

19. ABSTRACT (Continue on reverse if necessiry and identify by block number)

see attached report DTIC

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%I4

OFFICE OF NAVAL RESEARCH

Contract N00014-86-K-0547

R&T Code 4135011---02

Technical Report No. 3

Enantioselective Ring-cleavage of meso- Epoxideswith B1-Halodiisopinocampheylboranes

by

N. N. Joshi, M. Srebnik, and Herbert C. Brown

Prepared for Oral Presentation

at the196th Meeting of the

Journal of American Chemical Societyin

Los Angeles, CaliforniaSeptember 25-30, 1988

.. Purue University1. C. Brown and/R. B. Wetherill Laboratories of Chemistry

West Lafayette, Indiana 47907

May 17, 1988

Reproduction in whole or in part is permitted for

any purpose of the United States Government.

* This document has been approved for public release

and sale; its distribution is unlimited.

ABSTRACTI

Enantioselective Ring-Cleavage of meso-Epoxides NvithB- Halodlisopinocam pheylboranes.

N. N. Joshi, M. Srebnik, and H. C. Brown*11. C. Brown and R. B. Wetherill Laboratories of Chemistry,

Purdue University, West Lafayette, Indiana 49707.

A bstract: B-Hialodiisopinocarnpheylboranes, IPc2 BX, in particular tilebromide 1 b , and the iodide 1 c , differentiate betweeni the

eanriiotopic C-0 bonds of neso-epoxides to furnish 1,2-halohydrins-' of moderate to excellent enantiomeric purity. Thus (-)-(IR, 2R)-2-

bromocyclohexanol, (-)-( iR, 2R)-2-iodocyclohexanol, (-)-( IR, 2R)-2-

iodocycloliex-4-en-1 -ol and (-)-( iR, 2R)-2-bromocyclohex-4-eii- 1-olare obtained in 84%, 91%, 63% and 95% ee respectively from thecorresponding mneso -epoxides and haloborane reagents. Simplerecrystallization from pentane then gives halohydrins of essentially100% ee; cis-2-butene oxide and cis-3-hexene oxide furnish thecorresponding (iR, 2R)-iodohydrins in 78 and 69% ee respectively. IIIall cases the S carbon of the meso-epoxide is selectively cleaved. Thisis the first example of enantioselective ring cleavage of meso-

epoxides to obtain optically active 1 ,2-halohydrins. ~ ~ .~ 9

Acaeuion For

VTIS GRA&I* DTIC TAB E

Un~nnounced0

CPGr ByINPEr Distributionl/_____

r Availability Codes

j.Ava il and /orIDist Speoial

WS. X' .

M1 FPM yi n r - - -r -- U . 0

Enantioselective Ring-Cleavage of meso-Epoxides withB-Halodiisopinocampheylboranes.

N. N. Joshi, M. Srebnik, and I. C. Brown*H. C. Brown and R. B. Wetherill Laboratories of Chemistry,

Purdue University, West Lafayette, Indiana 49707.

Asymmetric synthesis starting from meso-compounds is anincreasingly important method for the preparation of optically activecompounds. Various chemical1 and enzymatic 2 procedures have beenutilized for such transformations. Surprisingly, not much attentionhas been given to the enantioselective ring-cleavage of meso-epoxides which would lead to several classes of importantcompounds. We now report the synthesis of optically active 1,2-halohydrins using B-halodiisopinocampheylboranes, lpc2 BX (la-c).

la X= CIlb X= Br

ic X= I

The cleavage of carbon-oxygen bonds with boron reagents, in* particular with trihaloboranes, is a well documented and established

procedure3. Ilowever, the high Lewis acidity of trihaloboranes andtheir tridentate nature can result in the unwanted rupture of bondsin compounds containing other sensitive functional groups. To

• increase the selectivity in carbon-oxygen bond cleavage,monohaloboranes in which two of the halogens on boron are replacedby alkyl 4 , alkoxy5 , thioalkyl 6, or nitrogen containing 7 groups haverecently been introduced. Such reagents indeed are selective and

* could by the proper choice of substituents cleave specific C-O bonds 7.Recently Guindon and co-workers reported 4 the stereospecific ring-

2

cleavage of various cyclic ethers with B-bromodimethylborane. Ofparticular consequence in the cleavage of epoxides with these type ofreagents is the fact that the halohydrin products are consistent witha predominantly SN 2 type mechanism proposed for suchreactions 4 ,7,8 . This suggests that the asymmetric version shouldproceed with a high degree of enantiotopic differentiation of the C-O

bonds of suitable meso-epoxides. Recently, the enantioselectivecleavage of cyclohexene oxide with thiols and azides in the presenceof zinc or copper tartrates has been successfully accomplished 9 .Except for this report, the cleavage of epoxides with chiral Lews acids

is an unexplored reaction. As part of our efforts in the field of* - asymmetric synthesis 1 0 , we are currently exploring reactions

involving boron based chiral Lewis acids. The present communicationdescribes our investigations on the enantioselective ring-opening of

. some meso-epoxides with B-halodiisopinocampheylboranes(pc2B X)ll, both enantiomers of which are readily available from

* either (+)- or (-)-ct-pinene.First we examined the reaction between cyclohexene oxide and

dlpc 2 BX (the superscript "d" indicates that the reagent is derived

from (+)-x-pinene) under various conditions, i.e, temperature,

solvent and molarity. Due to the labile nature of the products, a non-oxidative work-up was developed (eq 1).

dlpc2BX r2 (i) CH3CHO Oi

X (2) (HOCH 2 CH2)2 NH '", X

The course of the reaction was followed by I1B-NMR12. Thereaction is very fast (<5 rin) but proceeds with poor induction atOOC. Not surprisingly, an inverse relationship between enantiomeric

* excess (% ee) and the reaction temperature was found to exist. It wasestablished that Ipc2BCI. Ipc2BBr and Ipc2BI require -78oC/3 h,-100oC/2 h and -100oC/0.5 h respectively to furnish goodenantioselection. Furthermore, the reaction is independent of solvent

* or molarity. Since lb and ic provided superior results (at least in

3

the case of cyclohexene oxide), we used these reagents subsequentlyfor tile preparation of optically active halohydrins (Table I).

In general 14.1.01-oxaheptanes gave excellent initial opticalyields of halohydrins I 3 We also found that by simplerecrystallization from pentane, these could be upgraded to productsof essentially 100 % ee. Cyclopentene oxide gave reduced chemical aswell as optical yields. Simple acyclic epoxides were cleaved withoptical inductions intermediate between those realised 14 for theoxides of cyclohexene and cyclopentene. The % ee of the halohydrins(as their acetates) was determined using a chiral capillary GC column,Ni(HFB-I1R-Cam) 2

15.The absolute configuration of the cyclic halohydrins was

determined where possible by X-ray crystallography. The absoluteconfiguration of the acyclic compounds was elucidated as follows (eq

* 2).

OH X OTPC(1) n-Bu3SnH (2)

R R (2) R R

SOCOF3

Dehalogenation with tributylitin hydride gave the known secondaryalcohols 16 which were analysed as their TPC-derivatives 17 usingcapillary GC. Since the ineso-epoxides are opened in anantiperiplanar manner, determination of the absolute configurationof one asymmetric center establishes the configuration of the otheras well.

Of particular significance of this procedure is the fact that inaddition to high optical induction 1 8, the bond cleavage occurs in thesame absolute sense to furnish (IR, 2R)-halohydrins in all cases

. examined, with dlpc 2 BX 19 These results are consistent with thecleavage occuring in an anti manner with inversion at the S carbon of

" the meso-epoxides (eq 3).S

02."

0 4R dlpcBX R O

R _ Oil

J O (3)

S R X

In addition, closure of the acyclic chiral non-racemic halohydrins

yield the starting compounds, viz. a cis-epoxide, which would not be

the case had the opening proceeded in a syn manner (eq 4).

0

0 , (i)Ipc2BX<(4R 0 \--R (4)

1( R (2) Base 0 R

0R

In conclusion, the present methodology demonstrates the

feasibility of cleaving rneso-epoxides in an enantioselective manner

either at the R or S carbon by selecting the appropriate chiral

organoborane reagents. The transformation is general, providing

highly valuable difunctionalized compounds in good to excellent

enantiomeric purity from simple olefins. Synthesis of optically active

halohydrins is but one of the many possible applications which we

are currently exploring.

Acknowledgment: This work was supported in part by the Office of

Naval Research. We thank Dr. Phil Fanwick for the X-ray

* crystallographic analysis.

Ji:02

A-o%

References and Notes

(1) (a) Fujita, E.; Nagao, Y.; Seno, K.; Takao, S.; Miyasaka, M.; Kimura,

M.; Watson, W. 1t. J. Chem. Soc. Perkin Trans. 1 1981, 914. (b) Nagao,Y.; Ikeda, T.; Yagi, M.; Fujita, E.; Shiro, M. J. Am. Chem. Soc. 1982, 104,2079. (c) Osakada, K.; Obana, M.; Ikariya, T.; Saburi, M.; Yoshikawa, S.Tetrahedron Lett. 1981, 22, 4297. (d) Fujisawa, T.; Watanabe, M.;Sato, T. Chem. Lett. 1984, 2055.(2) Jakovac, I. J.; Goodbrand, H. B.; Lok, K. P.; Jones, J. B. J. Am. Chem.

Soc. 1982, 104, 4659.(3) Bhat, M. V.; Kulkarni, S. U. Synthesis 1983, 249.

(4) Guindon, Y.; Therien, M.; Girard, Y.; Yoakim, C. J. Org. Chem. 1987,

52, 1680 and references cited therein.(5) Boekman, R. K. Jr.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411.

* (6) (a) Williams, D. R.; Sakdarat, S. ibid. 1983, 24, 3965. (b) Corey, E.

%%% J.; Hua, D. H.; Seitz, S. P. ibid. 1984, 25, 3.(7) Bell, T. W.; Ciaccio, J. A. ibid. 1986, 27, 827.

(8) Parkee, R. E.; Isaacs, N. S. Chem Rev. 1959, 59, 737.(9) (a) Yamashita, H. Chemn. Left. 1987, 525. (b) Yamashita, II.;Mukaiyama, T. ibid 1985, 1643.

.(10) For recent reviews see: (a) Brown, 11. C.; Jadhav, P.K.; Singaram,

B. in Modern Synthetic Methods; R. Scheffold, Ed.; Springer-Verlag:Berlin; 1986, Vol. 4, p 307. (b) Srebnik, M.; Ramachandran, P. V.

K Aldrichimica Acta 1987, 20, 9.. (11) Ipc2BCl and Ipc2BBr were prepared by passing HCI or H11r

through a suspension of optically pure Ipc 2 BH in pentane at OOC.* Ipc2BI was made by reaction with 12. All the reagents were

recrystallized and stored as stock solutions in pentane.

(12) The reaction is quenched with pyridine which coordinates withthe unreacted haloborane (8 = 18-20 ppm) and not with the borinate

S(5 = 54 ppm) formed during the course of the reaction.(13) The preparation of (IR, 2R)-(-)-2-iodocyclohexanol: A

100 nil flask protected with a positive pressure of nitrogen, was

charged with Ipc2BI (11 Immol, 0.25 M in pentane). The solution was* cooled to -100oC and treated dropwise with cyclohexene oxide (10

mmol) dissolved in pentane (2 ml). After stirring for I h at -100oC,

0

6

.,the reaction was quenced by the addition of acetaldehyde (.8 ml,

excess). The mixture was allowed to warm gradually to roomtemperature and stirred for an additional I h. By that time 11 B-NMRindicated clean formation of boronate [R*OB(OEt)Ipc, 8 = 31 ppm]. The

reaction mixture was diluted with pentane (50 ml) and (reated withdiethanolamine (12 mmol, 4 M in TPF). After stirring for 30 min, theprecipitated boronate-diethanolamine complex was filterd off, thefiltrate was washed with water, brine, and dried over anhydrous

Na2SO4. The solution was concentrated under reduced pressure, andthe residue purified by column chromatography followed bycrystallization from pentane to provide the title compound (Table I,entry 3).(14) No attempt was made to achieve optimum results.(15) The column is available from: CC & CC (Capillary Column

* Complexation Chromatography),Postfach14, D7402, Kirchentellinsfort,F.R.G. The results of this study will be published seperately.(16) Brown, H. C.; Ayyangar, N. R.; Zweifel, G. J. Am. Chem. Soc. 1964,80, 397.(17) Hoones, E. A.; Peltzer, E. T.; Bada, J. L. J. Chromat. Sci. 1978, 16,556.(18) The origin of chirality in this transformation may be due tosimilar relative conformations of the two isopinocampheyl rings aswas postulated for asymmetric hydroborations. See, Brown, H1. C.;Jadhav, P. K.; Mandal, A. K. Tetrahedron 1981, 37, 3547.(19) The use of 'Ipc2BX (derived from (-)-ac-pinene) will obviouslyyield the corresponding (IS, 2S)-halohydrins.

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