1. Art and Diseño

Terrahedron Leuers, Vol. 35. No. 46, pp. 8541-8544, 1994
Pergamon
Elswier
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1,3-Asymmetric
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189I-X
Induction in Hydride Addition Reactions to P-Substituted Ketones.
A Model for Chin&y Transfer
David A. Evans,*
Depmmenr
Michael J. Dart, and Joseph L. Duffy
of Chemisrry, Harvard University. Cambridge. Massachusetts 02138, USA
We report the 1.3~asymmetric induction observed in the additions of various hydride reagents to /jAbstract:
substituted ketones. Both the nature of the &substituents and the size of the achiral alkyl group attached to the
carbonyl moiety have a significant effect on the direction aad degree of carbonyl diastereofaciai selectivity. A
revision of cram’s polar mode1 for 1.3~asymmetric induction is proposed to account for these results.
The purpose of this Letter is to highlight the turnover in stereoselectivity that is dependent upon the nahlre of
the B-substituent (alkyd vs. alkoxy) in the reductions of acyclic p-substituted ketones. Two representative
reductions that illustrate this observation are provided below (Scheme I).t.* We propose that electrostatic effects3
due to the presence of the phetemamm substituent are responsible for the observed reversal in z-facial selectivity,
rather than internal chelation.4 The stericallydemanding
bornhydride reagent, lithium tri-set-butylbomhyd,
has been compared with other common nucleophilic and electrophilic reducing agents, and is generally the most
stereoselective of the metal hydrides evaluated. Revision in the Cram polar and steric transition state models for
1,3-asymmeaic induction’. is presented to rationalize the trends observed for these and related processes.
Scheme I
k
-+
U(S-BU)@H
RL THF, -783‘c *
-pRL
RL=CMe2CH=Cb
0
‘&&-
(1)
Anbi:Spl=S2:oB
Ad
stereochamiatry
Ml: --
Canl
stelic Model
TBS
L&s-Bu)sBH
Me
-rpMe
yrJh
Rb
Rp - CMe3
TBB
THF. -78°C
- I-&Me&
-
yvq
yrJIy
Anursyn-a3:97
~c$J++&_
(2)
I
Crawl Polar Model
P_Alkoxyketones. Representative metal hydrides. including the sterically demanding reagents Li(s-BuTsBH
(L-Selectride) and Li(t-BuO)jAlH and the electrophilic reducing agents diisobutylalumiuum hydride @IBALE%)
and 9-borabicyclo[3.3. llnonane (9-BBN), were evaluated against a series of &alkoxyketones.5
Permutations in
the steric requirements of the Balky1 substituent (R@, the alkyl group appcnded to the carbonyl moiety (R), and
the hydmxyl protecting group (P) wen made.
Ketones 1 and 4 (eq 3) were selected to gauge the influence of the hydroxyl protecting group on the course of
the reaction. Reduction of these substrates with the illustrated hydride reagents (Table I) revealed that formation
of the 1.3~syn products 2 and 5 was preferred brespcctive of the nature of the hydroxyl protecting group. While
internal chelation4 of the substrate followed by external hydride delivery accounts for formation of the 1,3-syn
diastereomer,6 we believe that reaction through such a chelated intermediate, particularly in the strong donor
solvent THF. is not responsibk for the observed stemoinduction in these cases. This assertion is supported by the
fact that the highest syn selectivity shown in Table I (946) was achieved in the reduction of the silyl protected
hydroxy ketone 4.7 It is also significant that the highest levels 1,3-syn st ereoselection in these reactions were
achieved with L,i(s-Bu)3BH, a reagent which is generally not disposed toward chelation-controlled reduction.*
854 1
8542
Tdle
ow
OP
i-r&A,
Svn
2
5
1 P= PMB IpMoQC&i&Hp)
4 P =TBB (I-BuMezSi-)
I. Rdotions
d
hVab
Jx
3
6
(P : :A@
U(s-Bu)@H
Li(t-RuO)@H
DIBAL-H
9-BEN
(3)
Anff
Ketortos (eq 3).
p-Substituted
51 : 19
77 : 23
75: 22
59:43
5:s
(P-J-W
94: cs
57: 13
73: 27
50: 50
‘DclermkwdbyOLCulrlyr*dthupwlllrd~mtatt~
Tabk Il. lnnuuloeof Alkylaroup (R) on Rf@duabn (5q 4r
.M;w,.,
L
ax.x;tiph
syn
8
$1
14
7 R=Me
10 R-i-i%
13 R=t-Bu
8:9
RIM5
hydride
REx~:~*~(4)
Anti
9
12
15
11:12
R-I-R
14: 15
R-t-&
Li(MlJ~BH
51 : 49
79: 21
73: 27
U(t-BuO)sAlH 54: 44
89: 31
75: 25
DIBM-H
54; 45
50: 41
76: 24
51 : 49
xi:
46
66: 14
9.BBN
%aIumlnodty OLCmAydnd thaupurl(lrdmadbnmlxtums
In order to probe the influence of the alkyl substituent (R) appended to the carbonyl moiety, substrates 7,lO.
and 13 were subjected to the standard set of rcduction conditions (eq 4, Table II). These substrates were also
designed to evaluate the impact of the polar alkoxy substituent in a setting where the steric requirements of both &
substituents (C!HzCI-IzAr and OCHzAr) are comparable. The data in Table II document that enhanced selectivity
is observed as the size of the carbonyl substituent (R) is increased with the rerr-Bu ketone 13 generally exhibiting
face selectivity
the highest levels of syn dlastereoselection. In contrast, methyl ketone 7 exhibits poor cartiny
irrespective of the hydride source.
The influence of the size of the p-alkyl group (Re) on reaction diastereoselectivity
was examined in the
reduction of p-OTBS ketones 16,19,4, and 225b (eq 5, Table III). For both of the nucleophilic hydride
reagents, Li(s-l3u)3BH and Li(r-BuO)gAlH, a strong correlation between syn diastereoselection and the steric
demands of Ra is evident from the data.
0
Me
%
GMe
H-
Me*@
My&qp
(5)
16 RB=Me
17
18
19 Rg = cH&yPh
30
21
5
6
4 Fte=i-Pr
23
24
22 Rp = t-Bu
T5biaIII. Influenceof Substltutent
(Rg) In the Illustrated
HydrideReductions(eq Sy
hydride
17: 19
%-Me
290:21
Rg=ui@#h
Li(e-Bu)$H
Ll(t-BuO)+JH
74: 26
78: 22
92 : 08
93: 17
5:8
R@~i”
94: 06
23:24
= t-&l
97 :
03
87: 13
91 : 09
DBAL-H
69:
31
69:
31
73:
27
76 : 24
9-Bed
72:
26
87:
33
50:
60
79:
a Mastmlvily
wm delamllned by QLC dyxb
21
of ihe Mpwlned maabll mlxlur.
Based on the above observations, the following generalizations may be made: A) a turnover in carbonyi xfacial selectivity is observed upon changing the P-substituent (alkyl+OP);
B) enhanced 1,3-syn stereosclectivlty
in the reduction of kalkoxy ketones is observed with an increase in either the size of the B-alkyl moiety (Rp), the
acyl substituent (R), or the hydroxyl protecting group (P). A transition state model that accounts for this reversal
in diastereofacial selectivity as well as the other trends outlined above is currently lacking.
A revision of the Cram polar model for 1,3+tereoinduction Ia has been suggested in the preceding Letter.9
The specific objection to this model hinges on the utilization of eclipsed rather than staggered transition structures
(see Scheme I). As for predictive capacity, the Cram polar model does not correlate the influence of the carbonyl
substituent (R) on reaction diastereoselectivity (Table II). On the other hand, electrostatic effects are clearly
8543
playing an important role in governing the sense of asymmetric
induction as highlighted in the cases cited in eq 1
and 2. The following revision of Cram’s original polar model for 1,3-asymmetric induction is pmposed below.
Revised Polar Model. It is proposed that those transition structures wherein the fiarbon
<C# is oriented
perpendicular to the <Tframework of the carbonyl moiety be considered in recognition of the Felkin postulate,
supported by subsequent computational
studies, that the staggered conformation between Co and the trigonal
carbon undergoing reaction is preferred in such addition processes. to Staggered transition structures A and B
the dipoles associated
with C+-OR and the
account for the data reported in this study. In both of these SEUCN~,
In distinguishing
between these two alternatives, structure A
transforming carbonyl moiety sre stabilizing.
accounts for the dependence of 1,3-induction on the size of the carbonyl substituent (R) that is not handled by
Cram’s original proposal. The principal destabilizing element in B is the nonbonding m(R)C=O
interaction.
However, transition structure B might well bc favored in addition reactions to those substrates having sterically
demanding
Rp substituents (e.g. eq 2). For purposes of comparison, from the preceding Letter we have
concluded that the preferred transition structure in the Mukaiyama aldol addition to B-alkoxyaldehydes
is that
corresponding to B (R = H). where the indicated nonbonding interaction m(H)C=O
has been substantially
diminished.
Examination of potential transition states leading to the anti product diastereomerlt
lead us to
conclude that D is disfavored on the basis of steric considerations (Rgc)(R)C=O),
while destabilizing electrostatic
interactions are present in C. We also suggest that it is the electrostatic destabilization of C which differentiates the
present polar model from the steric model E provided in Scheme El (OR = RM).
Scheme II
on
OP
Finally, why is reaction diastereoselectivity
generally elevated with an increase in steric requirements of the
hydride reagent? We speculate that the illustrated atui, rather than g~h,Iu
relationship between nucleophile and
C8 is enforced with sterically demanding nucleophiles.
The Cram steric model (1968) for 1.3-induction
in
Steric Models for l&Asymmetric
Induction.
carbonyl addition has been widely recognized (Scheme I). la A less highly cited, but nonetheless significant study
by Jacques and co-workerstb in the same year rationalized the stcreochemical course of the hydride reductions of
P_alkyl substituted ketones (eq 1) through transition structures which may be closer to the consensus view of the
preferred geometries for these processes. lo In view of the relevance of the Jacques proposal to the present
investigation, it is reinterpreted here: A) Staggered rather than eclipsed transition structures are preferred having
anti orientation between C8 and the forming bond (Fe&in).
B) The dominant destabilizing
interactions are
between the acyl carbon substituent (R) and the ~substituents.
These interactions are minimized in E where the
illustrated relationship between (R) and the smallest @ubstituent @I in the present case) is established.
8544
A restatement of this model has recently been tqorted by Ohnold to account for the SteEOchemical course of
nucleophilic additions to @wbstituted acylsilanes (eq 6). Some years ago we also anploycd an analysis related to
that described by Jacques to rationalize the stcreochcrnical course of the illustrated hydroboration rea&on (eq 7).**
SehemeN
ohfw (1994)
Evans (1982)
The models for 1,3-asymmetric induction presented above and in the previous Letter rationalize the r-facial
selectivity that is observed in the absence of inte.rnal chelation in the nucleophilic
additions
to &substituted
aldehydes
and ketones. Ongoing theoretical and experimental studies to further investigate the nature of 1,3induction will be reported in due course.
References and Footnotes
1) For examples of nuclcqhilic additions to Balky1 substituted ketones w: (a) Leitereg. T. J_; Cram, D. J. /. Am. C&m. Sot.
2)
3)
4)
s)
6)
7)
8)
9)
10)
11)
12)
1968.90,4011-4018.
and 4019-4026. (b) Brienne, M-J.; Ouannea, C.; Jacques, J. Bull. Sot. 0&n. Fr. 1968.1036-1047.
(c)
Fleming I.; Lawrence, N. J. Chcm. Sot. Perkin Trans. I 1992.3309-33 18. (d) NaLada, M.: Urano. Y .: Kobaya&. S.: Ohno.
M. Tetrakdron Lett. 1994.3.5, 741-744.
For examples of the nucleophilic additions to protected p-aJkoxy ketones see: (a) Ukaji, Y; Kanda. K.: Yamameto. K,
Fujisawa, T. Chum. Lea 1998.597-600.
(b) Arco. M. J; Trammel, M-H.; White, J. D. 1. Org. Ckm. 1976.41.20752083. (c) Danishefsky. S. 1.: Annistead. D. M.; Wincott. F. E.: Selnick, H. G.: Hungate. R. J. Am. Chum. Sot. 1989.
111.2%7-2980.
For reductions of p-amino ketcmca see: (a) Pilli, R. A.; Russowsky. D.; Dias. L. C. 1. Ckm. Sot. Perkin
Trans. 1 1998.1213-1214.
(e) Tnnnontini, M. Synrhti 1982.605644.
Fur aa example of the lnflucnce of remute electrauatic effects on earbony x-facial r&ctivIty see; Wu. Y.-D.; Tucker,I. A.;
Ho&K. N. 1. Am. Chem. Sot. 1991.113.5018-5027.
(a) Cram, D. J.: Kopccky. K. R. J. Am. Ckm. Sot. 1959.81.2748-2755.
(b) Reetz. M. T. Act. Cheat. Res. 1993.26. 462468andrefuenccs
&cd tbetein. (c) Ager, D. J.: East, M. B. Tetrakdroti
1992,48 2803-2894.
(a) The raductions were carried out at the following tempemtuma in THFz Li(s-BuhBH and DIBAL-H at -78 Oc, Li(tBuG)3AlH and 9-BBN dimer at 0 “c to room tcmpemttue. Stemo&zn ical assignments htvolved calversiou of the l$diols
into the curwaponding accmnides or benzylidene &I,
and analysis by NMR spectroscopy (see nf. 9). (b) The DIBAL.-H
reduction of subatmtc 22 was cawied out in a vari#y of solvents to 8ive the folbwing ratios (l&yn
: l&z&): THF (76 : 24).
Et20 (63 : 27). CH2CI2 (62 : 38).andtolueme
(64 : 36).
(a) Fa a review of hydride additions to carbonyl annpounds see: Graves, N. in Co~e&nsivc
Or+c
Syntksis,;
Trost. B.
M.; Fleming. I. Eds.; Pergamon Press: New York. 1991: Vol 1. Chapter 1. (b) For examples of &as&rwAective
hydride
addi*
to ketoneaseez Nogradi. M. in Stereoselecrivc SynthesS. VCH. New York, 1986;Ch+u 3.2
(a) Bloch. R.: Gilbert, L.: Gii
C. Ternah&on Len. 1988.29. _loZl-1024. (b) Keck.G. E.: Andms, M. B.: CasteU&, S.
J. Am. Chem. Sot. 1989.111,8136-8141.Howeves.for mcentemdenca
in suppon of chelationby a vicinal OTBS ~poupsee:
(c) Chen, X.; Holtelano,E. R.; Eliel, B. L.; Frye, S. V. 1. Am. Chem. Sot. 1992,114, 1778-1784.
For examples illustrating the lack of chelation in the rcduelions of potected hydmxy-ketmx?s with Li(s-BuhBH &e: (a)
Takaha&i. T.; Miyazawa, M.; Tsuji, J. Tetrakdron L&r. 1985.26.5139-5142.
(b) Larcbeveque. M.; L&n&. J. J. Ghan.
Sot., Chem. Common. 1985.83-84.
Evans. D. A.; Duffy, J. L; Dart, M. J. Tetrakcdron Lcrr. 1994.35, thii issue.
(a) Cbereat, M.; Aelkin. H.; Prudent, N. Tetrakdron Lctt. 1968. 2199-2204. Fa compuuriollpl evidence supparine the
impormncc ofnonc&ps&
gtomenies in carbonyl add&ion seez (b) Anh. N. T.; Elsensteht. 0. None. 1. C/&n. 1977.1.61-70.
(c) Padden-Row. M. N.: Rondan. N. G.: Hot&, K. N. 1. AJPI.Chem. Sot. 1982.104.7162-7166.
(d) Houk. K. N.: PaddenRow, M. N.; Rondan, N. G.; Wu. Y.-D.; Brown, F. K.; Spellmeyer, D. C.; Mea. J. T.; Li. Y.; Loncbarich. R. J. Science
1986,231, 1108-1117.
Itisnotsuggts~edCCDDareeonly~ilionsllUeswhichmightgiverisetotheminorproductdiawer#wm
Itis
reasonablethateansiti~structurespoasessingagovckenlacionshipbetwwncgandnucleophileshwld~be~.
(a) Evans, D. A.; Bartroli, J.: Godel. T. Tewakdron
L&r. 1982.23. 45774580.
(b) For a relatedexnmplesee ref. Ic.
(c)COmputatiaRalJupportfa~modelpopostdbyushesbeen~byHouk,rcf.lOd
(Re&ved
in UsA
24 August
1994; revised 15 September 1994; accepted 21 September 1994)