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Highly Enantioselective Protonation of Thiol Ester Enolates.

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14. The initially formed oxonium ion is attacked from above
by the pyrrole ring D to give 14 with a p-directed H atom on
C19 (or vice versa). This step is followed by numerous reversible suprafacial [I ,5] sigmatropic shifts to provide the
spiro o complex 15 and subsequently the uroporphyrinogen
I11 o complex 16, in which the H atom on C19 is now in the
a position (or vice versa). Abstraction of this proton by a
suitably placed base in the enzymic cleft-presumably the
anion of the acid that protonated 1 in the first step -leads to
formation of uroporphyrinogen 111 (2) in an irreversible reaction.
1
2
[I] A. R. Battershy, C J. R. Fookes. K. E.Gustafson-Potter, E. McDonald,
G. W. J. Matchham. J. Chem. Sot. Perkin Truns. 1 1982, 2427~~2444.
[2] L Bogorad, J. Bid. Chem. 1958, 233. 501 509.
[3] L. Bogorad. J. Bid. Chem. 1958. 233. 510-515.
[4] a) A. R. Battersby, F. J. Leeper, Cheni. Rev. 1990, 90. 1261 -1274; b) J. H.
Mathewson. A. H. Corwin, J. A m . Chem. Soc. 1961, 83, 135-137.
[ S ] a ) A . H. Jackson, W. Lertwanawatdna, R. K. Pandey. K. R. N. Rao, J.
Chem. Soc. Perkrn Truns. 1 1989. 374-315; b) A. R. Battershy, M. G.
Baker, H. A. Broadbend, C. J. R. Fookes. F.J. Leeper, rhid. 1987, 20272028; c) A. R. Battersby. H. A. Broadbend. C. J. R. Fookes, J. Chrm. Soc.
Chem. Commun. 1983. 1240- 1242.
[6] a) A. I. Scott, 7i,rrukedron 1992,48,2559- 2578; b) A. I. Scott. Acc. Chem.
Res. 1990, 23. 308-317.
[7] L. F. Tietze, H. Geissler, Anpiwv. Chem. 1993, 105, 1087: Angew. Chem. In<.
Ed. Engl. 1993. 32. 1040.
181 The transition structures were optimized with the NSOlA routine (M. J. D.
Powell, J. Chandresekar. P. H. M. Budzelaar. T Clark) of the VAMP
software package and characterized with FORCE calculations: J. W.
Mclver, A. Kormonicki, J. A m . Chrm. Soc. 1972. Y4. 2625-2633.
I
A m . Chem.
[9] M. J. S. Dewdr, E. G. Zoebisch. E. F. Healy. J. J. P. Stewart. .
So<..1985. 107, 3902-3909.
[lo] D. Mauzerall. J. A m . Cliem. Soc. 1960. 82, 2601-2605.
~
Highly Enantioselective Protonation of Thiol
Ester Enolates
By Charles Fehr,* Isabelle Stempj; and Jose Galindo
H
A
uroporphyrinogen 111 u complex
hydroxymethylbilan f
16
11
Enantioselective protonation of achiral enolates using an
efficient and synthetically useful chiral proton source has
long been discussed and has great synthetic potential. Recent
progress in this field" -31 has led to enantioselectivities of up
to 91 % ee.['] From both preparative and mechanistic standpoints greater enantiofacial discrimination would be highly
desirable. Our efforts have concentrated on the preparation
of enantiomerically pure (R)- and (5)-a-cyclogeranic acid
((R)-1 and (S)-l)r41which are pivotal, versatile intermediates
in the synthesis of fragences and in medicinal chemistry.[']
0
uroporphyrinogen I a complex
Spiro
u complex 15
14
Scheme 1. Postulated biosynthetic route to uroporphyrinogen 111 (2) from hydroxymethylbilan ( I ) ( A : CH,CO,H, P: (CH,),CO,H).
In summary it can be said that nature had to find a way to
improve the unselective synthesis of uroporphyrinogen I11 in
the primordial broth. This was accomplished with the formation of the enzyme cosynthetase, which, as we assume, prohibits the abstraction of a proton of the initially formed
uroporphyrinogen I o complex to give uroporphyrinogen I,
whilst the abstraction of a proton from the uroporphyrinogen 111 o complex, which is formed in equilibrium, is enhanced giving uroporphyrinogen 111. The differentiation of
the protons in the o complexes by the enzyme is possible as
they have opposite orientations.
Received: February 12, 1993 [Z 5865 IE]
German version. A n p r w . Chem. 1993, 105. 1090
1042
6
3 VCH
Verlupspesells~hufrmhH. 0-6945f Weinheim, I993
0
We herein report the large-scale synthesis of thiol esters
(5)-4, (S)-S, and (R)-4 by an unprecedentedly efficient enantioselective protonation (99 YOee) of enolates 4(Li) and 5(Li)
with readily accessible and easily recoverable (-)- and (+)N-isopropylephedrine (( -)-7 and (+)-7)['] as the chiral proton source.
The transformations of (R)-4 and (S)-4 into (R)-1 and
(S)-1 as well as the perfume components (R)-and (S)-methyla-cyclogeranate ((R)-2 and (S)-2)and (S)-cc-damascone ( ( S ) 11)I1] under nonracemizing conditions (see below) demonstrate the importance of the new enantioselective protonation
When racemic methyl a-cyclogeranate ( ( R ,S)-2) was deprotonated with nBuLi and the resulting enolate Z(Li)['I (Z/
[*I Dr. C. Fehr. Dr. I. Stempf"'. J. Galindo
Firmenich SA. Research Laboratories
P.O. Box 239. CH-1211 Geneva 8 (Switzerland)
Telefax: Int. code +(22)7803334
['I Postdoctoral fellow at Firmenich SA (1990-1991).
+
0~770-OX331Y3/0707-/042$ 10.00 .ZS,O
Anpeti.. Chem. Inr. Ed. Engl. 1993. 32, No. 7
(R,S)-2 - (R,S)-6
X=OMe
2(Li) - 6(Li)
2
E=19:1)[*] protonated with (-)-7, (S)-2was obtained with
36% eeC9.l o l (Table 1, entry 1). This low enantiofacial discrimination may be due to an insufficient structural differentiation of the enolate substituents on C1 (OLi vs. OMe) for
efficient enantiotopic recognition, and an overly rapid protonation of 2(Li) due to the high pK, of 2. Therefore, phenyl
ester 3 and the aryl thiol esters 4,['] 5, and 6 were chosen as
substrates.
Table 1 . Enantioselective protonation of enolates 2(Li)-6(Li).
~~~~
enantioselective addition. In order to test this possibility,
thiol ester enolate 4(Li) was treated with lithium 2-naphthyl
thiolate prior to protonation with (-)-7. The same experiment was then repeated with thiol ester enolate 5(Li) and
lithium phenyl thiolate. In both cases the thiol ester corresponding to the original enolate was isolated with 99% ee.
The absence of scrambling leads us to the conclusion that a
free ketene is not involved. Nevertheless, the addition of
lithium phenyl thiolate to 8 in the presence of (-)-7 was also
investigated and showed the same enantiofacial preference
as enolate 4(Li) when treated with ( -)-7.IL4]
A prerequisite for the exceptionally high enantioselectivities obtained in the protonation of aryl thiol ester enolates is
the formation of a unique 2 enolate possessing appropriately differentiated enolate substituents (OLi vs. SAr)," 51 coupled with the strong coordination and chelation abilities of
ephedrine derivatives.[I6l Presumably, protonating agent
(-)-7 or (+)-7 rapidly forms a 1 :1 complex with the enolate
leading to a chiral enol/enolate "hybrid" structure," followed by an irreversible, stereocontrolled C-protonation via
an ordered, conformationally rigid transition
3a* 14]
The synthetic value of thiol esters (R)-4 and (S)-4 as versatile chiral building blocks is demonstrated by their ready
conversion into (R)-and (S)-a-cyclogeranic acids ((R)-1 and
(S)-l)["I ( 2 98% ee),['O1 methyl esters (R)-2 and (S)-2
( 2 98 % ee), (S)-a-cyclocitral
([a];" = - 743
( c = 0.05 in CHCI,), 98% ee)IIO1 and (S)-a-damascone
(ll)['I (99% ee)["l (Scheme 1). The saponification ( S ) -
~
ee
Entry Substrate
Reactlon conditions
(equiv; T["C] (r[m~n]))
1
2
2
3
3
4
4
5
6
4
1 ) nBuLi (2.0; -78 (240))
2) (-)-7 (2.6; - 100 (60) - 10 (25))
1) nBuLi (3.0; -100 (180))
2) (-)-7 (4.0; - 100 (60) - 10 (25))
1) nBuLi (1.5; -100 (120))[a],
2) (-)-7 (2.0; - 100 (60) - 10 (25))
1) [b], 2) (+)-7 (2.0; - 100 (60) - 10 ( 2 5 ) )
1) [h], 2) (-)-7 (2.0; - 100 (60) + -10 (25))
l)nBuLi(1.7; -100(120))
2)(-)-7(2.3; -l00(60)+ -10(25))
5
6
l"~1
-
- -
36 ( S )
Yield
[cl 1x1
~
77 ( S )
-
99(S)
87
87
82
99 ( R )
99 ( S )
90(S)
~
[a] Use of 1.1 equiv nBuLi gave 9 7 % ee. [h] As in entry 3. [c] After distillation.
To ensure efficient deprotonation, the starting ester was
deprotonated with 1.5-3 equiv nBuLi in THF/hexane at
- 100 "C (liquid N,/Et,O).['ll
Protonation of 3(Li) with
(-)-7 at -100°C (1 h), followed by gradual warming to
- 10°C (25 min) afforded (S)-3 with 77% ee"'] (Table 1,
entry 2). In line with our expectations, thiol esters 4-6 gave
even better results (Table I , entries 3-6): we were very gratified to find an exceptionally high enantioselectivity of more
than 200: 1[ I z 1 for the protonation of both phenyl thiol ester
enolate 4(Li)[l3l and 2-naphthyl thiol ester enolate 5(Li). In
addition, when (-)-7 and (+)-7 were used, (S)-4 and (R)-4,
respectively, were obtained with 99% ee (Table 1 , entries 3
and 4). These values are the highest enantioselectivities yet
reported for enolate protonations.
The propensity of the thiol ester enolates to form ketenes
by elimination of thiolate, and the fact that ketene 8 was
detected by GC (z10'/0) in all cases studied, led us to also
consider an alternative mechanism involving elimination/
w
8
Angew. C%pm.fnr. Ed. Engl. 1993, 32. No. 7
$3 YCH
n
(S)-2
(S)-9
(S)-lO
Scheme 1. (R)-4 and (S)-4 as new chiral building blocks (only ( S ) enantiomers
are represented). a) H,O, (6.0 equiv), LiOH (3.0 equiv), aq EtOH, 80°C.
90 min; b) K,CO, (1.2 equiv). Me1 (1.2 equiv), acetone, 60'C, 90 min; c )
LiA!H,(l.Oequiv), Et,O, 20°C. 1 h; d)(COCI), (1.5equiv). NEt, (S.0equiv).
dimethyl sulfoxide, (2.4 equiv), -70 -t 0 "C, 15 min, (Swern oxidation); e)
H,C=CHCH,MgCI (1.70equiv). LDA (l.OSequiv), T H E 35°C. 1 h; f ) ToSOH (cat.), toluene, 20°C. 15 h.
4 -+ (S)-1 and the mono-Grignard reaction (S)-4 --t (S)-11
merit special comments: the use of LiOOH for the hydrolysis
of (R)-and (S)-4 without racemization is new.[17.I s ] It is not
yet clear whether this reaction proceeds via an acyl sulfoxide,
followed by O(S) to O(C) rearrangement and hydrolysis of
the sulfinyl esterfLg1
or by normal B,,2 (base-catalyzed acyl
cleavage via a tetrahedral intermediate) nucleophilic substitution. Conversion of (S)-4 to (S)-a-damascone ((S)-ll)["
with allylmagnesium chloride/LDA proceeds by regioselective deprotonation of the product ketone which favorably
competes with nucleophilic attack of a second molecule of
the Grignard compound.["] The fact that no racemization is
observed clearly demonstrates that thiol ester (S)-4 is not
deprotonated during this process, thus considerably enlarging the scope of possible transformations starting from ( R ) and (S)-4.
Veria~.~ge.sellschafi
mhH, 0-69451 Weinherm, 1993
0S70-0833/93/0707-1043$ /0.00+ .25/0
1043
Experimental Procedure
(S)-4): A solution of(R.S)-4 (40.0 g, 153.8 mmol) in THF(450 mL) wascooled
at - 100 to - 110 C (Et,O, liquid N,)and treated with 1.92 M nBuLi in hexane
(120.2 mL, 230.8 mmol) (40 min. T 5 - 100 C). The solution was stirred hetween - 105 and - 100 C for 2 h. A solution of (-)-7 (63.7 g, 307.7 mmol) in
T H F (100 mL) was then added over 50 min at - 100 ,C. The reaction mixture
was cooled to between - 102 and - 100 C for 1 h and than allowed to warm
up to - 10 Cover 25 min. The mixture was poured into vigorously stirred 5%
aq NaOH and extracted with Et,O. The organic phase was washed successively
with H,O, 5 % aq HCI. H,O. Saturated NaHCO,, and saturated NaCl solution,
dried over Na,SO,, and concentrated. Distillation ( 1 lO-C!0.02 Torr) afforded
421 (CHCI,,
(S)-4 (34.92 g, 87%. 2 9 7 % hy GC. 99% ce[12]. [XI;"=c = 0.04). The combined acidic aqueous phases were hasified (10% KOH).
extracted (Et20). and distilled 90'Ci2 Torr) to afford recovered (-)-7 (62.4 g.
98%). -(S)-4: 'H NMR (360 MHz. CDCI,, 2 5 . C ) : 6 = 0.96(s. 3 H): 1.05 (s,
3 H ) ; l Zl(m.1 H),1.79(hr.s.3H),I.91(m.l
H).1.98-2.lX(m.2H),2.X6(br.
s. 1 H), 5.64 (hr. s, 1 H). 7.38 (s. 5 H). IR (neat): F = 2970. 1705. 14x0. 1440,
980cm-'. MS (70eV): nz/z(%): 151 (13). 123 (100). 109(12), 107(10). 91 (9).
81 (33).
( R ) - 4 ( ~ 9 7 % p u r e h y G C ; Y 9 % ~ ~ . e [ 1 2 ] ,=
[ 1 ] ~427(CHCI,.c
0
=0.06))was
obtained accordingly when ( + ) - 7 was used.
+
[lb] E M. Arnett. M A. Nichols. A. T. McPhail. J Am. Chrin. Su.1990, //Z,
7059.
[I71 Other conditions tested (aq LiOH. dimethoxyethane (DME), 85 C ; aq.
NaOH. THF, 65 ' C ) were inefficient.
[I81 Similar conditions have been previously applied i n the saponification of
esters and amides: E. J. Corey. S. Kim. S. Yoo, K. C. Nicolaou. L. S.
Melvin. Jr.. D. J. Brunelle. J. R. Falch. E. Tribulski, R . Lett. P. W, Sheldrake. J A m Chem. Soc. 1978. 100.4620: D. A. Evans. T. C. Britton, J. A.
Ellmann, f i w u / w h m Le11. 1987, 28, 6141, W. Oppolzer, J. Bldgg, I. Rodriguez. E.Walther, J. An?. Chem. SOC.1990. ll?. 2767.
I191 K. Schank. A. Frisch. B. Zwanenburg, J. Org. Cheni. 1983, 48. 4580.
[20] C. Fehr, .I.Galindo. H ~ YChim.
.
Acru 1986. 69, 228.
Enantioselective Addition of Aromatic Thiols
to a Ketene
By Charles Fehr,* isubelle StempJ and Josk Galindo
Reiceived: January 26, 1993 [Z 58321E]
German version: Angeir. Chcm. 1993, 10.5 1091
[ I ] a) C. Fehr. Chimiu 1991,45. 253; h) C. Fehr, J. Galindo. J A m Chem. Soc.
1988. 110.6909.
[ 2 ] S. Takeuchi. N . Miyoshi, Y Ohgo. C'hm7. Let). 1992, 551 : S. Takeuchi. N.
Miyoshi, H. HirdPd, H. Hayashida, Y. Ohgo. Bull. C h [ w . Soc. Jpn. 1992,
65. 2001; 0.
Piva. 1:P. Pete. TeeiruheihedronLrit. 1990.3I. 51 57: D. Potin. K.
Williams, J. Rebek, Jr.. Angew. Chem. 1990, 102, 1485: Angeiv. Chrm. Inr.
Ed. EngL 1990,29, 1420.
[3] a ) E. Vedejs. N. Lee. J An7. Cheni. Sw. 1991. 113. 5483. b) F. Henin. J.
Muzart. J.-P. Pete. A.M'Boungou-M'passi. H. Rau. Angeir. Chem 1991,
/03, 460; Angew. Chon. Inr. E d Engl. 1991, 30. 416: K. Matsumoto, H.
Ohta, Terruherlron Lett. 1991. 32. 4729; A. Kumar, R. V. Salunkhe. R. A.
Rane, S. Y Dike. J Chm7. Suc. Chm7. Cunm?un. 1991,485: U. Gerlach. S.
Hiinig, Angew. Chem. 1987, 99. 1313; Angeii. Chem. Inr. Ed. Engl. 1987.
Peschard.
26. 1283, L. Duhamel, P. Duhamel. S. Fouquai. J. Eddine. 0.
J.-C. Plaquevent. A. RaVard, R. Solhard, J.-Y. Valnot. H. Vincens. Tkwuhedrun 1988.44, 5495 and references therein; c) for enzyme or antibody-catalyzed enantioselective C-protonations ofenols (up to 9 6 % w): L L . Reymond. K. D. Janda. R. A. Lerner. J A m . Chmi. Soc. 1992, 114.2257: K.
Matsumoto. S. Tsutsumi. T. Ihori. H. Ohta, ihid. 1990, If?, 9614: review:
H. Waldmann. Nuchr. Chem. Terh. Lab. 1991. 39. 413.
[4] For the resolution of racemic 1. see: D. J. Bennet. G. R. Ramage. J. L.
Simonsen. J Chem. Suc. 1940. 418; and ref [Sh].
[5] a ) T. Matsumoto. S. Usui. BUN.Chum. Soc. Jpn. 1979.52.212;R. Buchecker. R. Egli. H. Regel-Wild, C. Tscharner, C. H. Eugster, G. Uhde, G.
Ohloff. Heli,. Chin?. Acru 1973. 56. 2548: T. Matsumoto. S. Usui, Chrm.
Lett. 1978. 105; Y. Masaki. K. Hashimoto. H. Iwai. K. Kaji, ihid. 1978,
1203; h) T Oritani. K. Yamashita. Agnc Biol. Chcm. 1987. 5 / , 1271; and
ref. [la].
[b] (R)-2 has a precious flowery, fruity damascone-like fragrance. whereas
(S)-2 is characterized by a green. metallic. minty, camphoraceous note,
see: C. Fehr. I. Stempf. J. Galindo, Swiss Patent application 13. October
1992.
[7] C . Fehr, J. Galindo. J. Org. Chem 1988, 53. 1828.
[XI E:Z ratios determined by NO€ experiments o n the corresponding Me&
ketene acetals.
[Y] Complexation of enolate 2(Li) with (-)-7(Li) or (-)-7(MgCI) (metalated
(-)-7) prior to protonation with (-)-7 [I h] did not bring any improvement (36% er and < 5 % P P ) .
[lo] Determined by gas chromatography using permethylated P-cyclodextrin
in OV-1701 as chiral stationary phase; column length: 12 m. For use of
short columns, see. M. Lindstrom, J High Resolrrt. Chromurogr. 1991, 14,
765.
[ I l l Above -80 , the enolates 3(Li)~-6(Li)
obtained are converted via ketene
8(7] to 1-(2.6.6-trimethyl-2-cyclohexenyl)-1-pentanone.
[I21 Determined by conversion of 3 - 6 into (2.6.6-trimethyl-2-cyclohexenyl)
methyl acetate [I) LiAIH,. Et,O. 2 ) AcCI. pyridine. Et,O] and GC measurements using permethylated I(-cyclodextrin in OV-1701 as chiral stationary phase.
[I31 Trapping of 4(Li) with Me,SiCI gives almost exclusively ( Z )ketene thiol
acetate ( Z ; E 2 98: 2 by GC). After distillation. the ZIEratio is 83: I 7 (GC
and NOE experiments).
[14] See C . Fehr, I. Stempf, J. Galindo. Angcit. Chen?. 1993, 105. 1093; A n g ( w
Chtvm Int. Ed. En,ql. 1993, 32, 1044.
[IS] The pK, of the substrate and the nucleofugal properties of X are also
critical. Protonation of the cr-cyclothiogeranate enolate with X=SnBu
showed low enantioselectivity (30% w).
1044
t:.i'
V C H Verl(i~.r~e.sellsc/iufr
mhH, 0-69451 Wemheim, I993
In the preceding communication, we reported the enantioselective protonation of Z thiol ester enolates 1(Li) and
2(Li) with 99% ee, using (+)- o r (-)-N-isopropylephedrine
(( +)-4 or (-)-4) as the chirdl proton source.111A prerequisite for the success of this process is the highly stereoselective
formation of a Z thiol ester enolate at low temperature, since
above -80°C enolates 1(Li) and 2(Li) eliminate lithium
thiolate to give ketene 5.
Both preparative and mechanistic considerations directed
our interest to a hitherto unknown reaction, the enantioselective addition of a thiolate to a ketene (e.g. 5 -1(Li)
- + ( - ) - I or (+)-1) in the presence of a chiral proton
donor.[', 31 We now describe the successful realization of this
procedure (up to 97% re) and its extension to a catalytic
version (up to 9 0 % ee with 2-5 mol% chiral catalyst).
ULi) - 3(Li)
5
Ar = Ph
1
2-naphthyl 2
p-C1-C,H4 3
Scheme 1. Enantioselective addition of thiols to 5. The deprotonation of
racemic I and 2 is described in ref. [I j.
Slow addition (3-4 h) of (-)-4 to a solution of 5 and
lithium thiophenoxide in T H F at - 55 "C afforded thiol ester
(S)-1 in 84% yield and 95 % re (Table 1, entry 1). Thiol ester
( S ) - 3 was obtained analogously in 83 YOyield and 97 % ee
from 5 and lithiump-chlorothiophenoxide (Table 1, entry 2).
Since under these conditions the equilibrium between 5 and
l(Li) (or 3(Li)) lies on the side of 5, the reaction rate is
controlled by the addition of (-)-4. This allows rapid and
irreversible C-protonation of the incipient enolate. In this
[*I
['I
Dr. C. Fehr. Dr. 1. Stempf."' .I.
Galindo
Firmenich SA. Research Laboratories
P.O. Box 239, CH-I211 Geneva 8 (Switzerland)
Telefax. Int. code + (22)7803334
Postdoctoral fellow at Firmenich SA (1990 -1991)
057U-OK33/93~0707-1044
S IO.fXJ+.?S/O
Angew. C h u m I n r . Ed. EngI. 1993. 32, N o . 7
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