Synthesis of enantiopure C2-symmetric VERDI disulfonamides and their application to the catalytic enantioselective addition of diethylzinc to aromatic and aliphatic aldehydes

Article abstract of DOI:10.1021/jo990984e

The enantiopure disulfonamides 7a-c have been prepared from the C₂- symmetric diketone 2, a starting material conveniently accessible from the 'dimerization' of (+)-verbenone. These ligands, when treated with titanium isopropoxide and diethylzinc, function as catalysts for the enantioselective alkylation of aldehydes. Stereoselectivity levels ranging from 72 to 98% ee are seen depending on the structural characteristics of the aldehyde. In all cases, the absolute configuration of the carbinol product is R. A working mechanistic model is advanced for the purpose of rationalizing the high levels and direction of asymmetric induction exhibited by these VerDI catalysts.

Full text of DOI:10.1021/jo990984e

J . Org. Chem. 1999, 64, 7929-7934
7929
Syn th esis of En a n tiop u r e C
2
-Sym m etr ic VERDI Disu lfon a m id es
a n d Th eir Ap p lica tion to th e Ca ta lytic En a n tioselective Ad d ition
of Dieth ylzin c to Ar om a tic a n d Alip h a tic Ald eh yd es
Leo A. Paquette* and Renjie Zhou
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received J une 21, 1999
2
The enantiopure disulfonamides 7a -c have been prepared from the C -symmetric diketone 2, a
starting material conveniently accessible from the “dimerization” of (+)-verbenone. These ligands,
when treated with titanium isopropoxide and diethylzinc, function as catalysts for the enantiose-
lective alkylation of aldehydes. Stereoselectivity levels ranging from 72 to 98% ee are seen depending
on the structural characteristics of the aldehyde. In all cases, the absolute configuration of the
carbinol product is R. A working mechanistic model is advanced for the purpose of rationalizing
the high levels and direction of asymmetric induction exhibited by these VERDI catalysts.
Asymmetric synthesis, when realized by means of
molecular catalysis, is a rich, fundamental, and attractive
area of investigation. Although various strategies and
1
,2
methodologies have been developed, enantioselective
bond formation remains one of the more vigorously
pursued areas of investigation because of a continuing
quest for improvement.3 The necessary discrimination
between enantiotopic atoms, groups, or faces in achiral
molecules requires the development of efficient and
effective catalyst systems. In this connection, the pos-
sibility of bringing together two molecules of inexpensive,
-8
9
enantiopure (+)-verbenone (1) in a manner that leads
2
conveniently to C -symmetric aryl-conjoined “dimers” has
1
0
recently been realized in this laboratory. The new
molecular scaffolds represented by 2 and 3, referred to
as VERDI reagents to reflect their origin (VERbenone
DImers), are currently being crafted into catalysts that
will hopefully have broad-ranging potential application
for high-level enantioselection in a variety of reactions.
So extensively studied has been the addition of dieth-
ylzinc to aldehydes in the presence of small quantities
of chiral ligands that this particular reaction has come
examples.18 In this paper, we report on the structural
features of diol 3, the preparation of several structurally
related disulfonamides, and the ability of titanium iso-
propoxide complexes of the latter VERDI ligands to bring
about the title reaction in an enantiocontrolled manner.
Resu lts a n d Discu ssion
Str u ctu r a l Con sid er a tion s. In general terms, the
tetrasubstitution pattern of the central benzene ring in
VERDI systems can be expected to introduce substantial
to be regarded as a good first test of the serviceability of
Mechanistic studies of this
broadly useful reaction have revealed an appreciable
new catalyst systems.1
1-16
sensitivity to the steric and electronic properties of the
(11) â-Aminol alcohols: (a) Zhu, H.-J .; Zhao, B.-T.; Dai, W.-M.; Zhou,
J .; Hao, X.-J . Tetrahedron: Asymmetry 1998, 9, 2879. (b) Bolm, C.;
Mu n˜ iz-Fern a´ ndez, K.; Seger, A.; Raabe, G.; G u¨ nther, K. J . Org. Chem.
various ligand types.17 Ample consideration has also been
accorded to transition state models for a variety of
1
998, 63, 7860. (c) Tanner, D.; Kornø, H. T.; Guijarro, D.; Andersson,
P. G. Tetrahedron 1998, 54, 14213. (d) Yang, X.; Shen, J .; Da, C.; Wang,
R.; Choi, M. C. K.; Yang, L.; Wong, K.-y. Tetrahedron: Asymmetry
1999, 10, 133. (e) Zhang, H.; Chan, K. S. J . Chem. Soc., Perkin Trans.
1 1999, 381. (f) Palmieri, G. Eur. J . Org. Chem. 1999, 805, 5. (g)
Kitamura, M.; Oka, H.; Noyori, R. Tetrahedron 1999, 55, 3605.
(12) Diamines: (a) Asami, M.; Watanabe, H.; Honda, K.; Inoue, S.
Tetrahedron: Asymmetry 1998, 9, 4165. (b) Vyskocil, S.; J aracz, S.;
Smrcina, M.; Sticha, M.; Hanus, V.; Polasek, M.; Kocovsky, P. J . Org.
Chem. 1998, 63, 7727.
(13) Diols: (a) Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl.
1991, 30, 1321. (b) Seebach, D.; Behrendt, L.; Felix, D. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 1008. (c) Seebach, D.; Beck, A. K.; Schmidt,
B.; Wang, Y. M. Tetrahedron 1994, 50, 4363. (d) Waldmann, H.;
Weigerding, M.; Dreisbach, C.; Wandrey, C. Helv. Chim. Acta 1994,
77, 2111. (e) Oguni, N.; Satoh, N.; Fujii, H. Synlett 1995, 1043.
(14) Binaphthols: (a) Zhang, F.-Y.; Yip, C.-W.; Cao, R.; Chan, A. S.
C. Tetrahedron: Asymmetry 1997, 8, 585. (b) Mori, M.; Nakai, T.
Tetrahedron Lett. 1997, 38, 6233.
(
1) Noyori, R., Ed. Asymmetric Catalysis in Organic Synthesis; J ohn
Wiley and Sons: New York, 1994.
2) Ojima, I., Ed., Catalytic Asymmetric Synthesis; VCH Publish-
ers: New York, 1993.
3) Helmchen, G.; Hoffmann, R. W.; Mulzer, J .; Schaumann, E., Eds.
Methods of Organic Chemistry (Houben-Weyl); Thieme: Stuttgart,
996; Vol. E21.
4) Nogradi, M. Stereoselective Synthesis: A Practical Approach; 2nd
ed.; VCH Publishers: New York, 1995.
5) Procter, G. Asymmetric Synthesis; Oxford University Press: New
York, 1996.
(
(
1
(
(
(
6) Atkinson, R. S. Stereoselective Synthesis, J ohn Wiley and Sons:
Chichester, 1995.
(
7) Ager, D. J .; East, M. B. Asymmetric Synthetic Methodology; CRC
Press: Boca Raton, FL, 1996.
8) Hayashi T.; Tomioka, K.; Yonemitsu, O. Asymmetric Synthesis;
Gordon and Breach: Amsterdam, 1998.
9) Sivik, M. R.; Stanton, K. J .; Paquette, L. A. Org. Synth. 1995,
2, 57.
10) Paquette, L. A.; Bzowej, E. I.; Branan, B. M.; Stanton, K. J . J .
Org. Chem. 1995, 60, 7277.
(
(
(15) (a) Aminophosphines: Mori, T.; Kosaka, K.; Nakagawa, Y.;
Nagaoka, Y.; Tomioka, K. Tetrahedron: Asymmetry 1998, 9, 3175. (b)
Aminoselenides: Santi, C.; Wirth, T. Tetrahedron: Asymmetry 1999,
10, 1019.
7
(
1
0.1021/jo990984e CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/29/1999

7
930 J . Org. Chem., Vol. 64, No. 21, 1999
Paquette and Zhou
F igu r e 1. ORTEP diagram of 3: (a) front view; (b) side view.
structural rigidity and a unique geometrical relationship
between the ligating centers. In an effort to gain insight
into the bite angle characteristic of the two hydroxyl
groups in 3, we have pursued an X-ray crystallographic
analysis of this ligand. Examination of molecular models
indicated that the chelate bite angle was considerably
in excess of 90°. The advantages potentially associated
Sch em e 1
1
9
with wide bite angles have previously been discussed.
Two views of the experimentally determined structural
topography of 3 are provided in Figure 1. The O1-C1-
C2-O2 dihedral angle of interest is 101.95°. It will be
1
20
noted that a
3
/ hydrate is involved. Although the
resultant hydrogen bonding may affect the hydroxyl
group positions to a small extent, it is quite clear that
the natural bite angle exceeds 100°. Our expectation is
that diamines related to 3 will share the same backbone
constraints and valence angles. At issue, of course, is
whether these structural features might lead to improved
enantioselectivity in catalytic operations.
Syn th etic Stu d ies. When the dioxime of 2 proved to
be too insoluble for convenient processing,21 recourse was
(
16) Disulfonamides: (a) Yoshioka, M.; Kawakita, T.; Ohno, M.
Tetrahedron Lett. 1989, 30, 1657. (b) Takahashi, H.; Kawakita, T.;
Yoshioka, M.; Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1989, 30,
7
095. (c) Takashashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.;
Kobayashi, S. Tetrahedron 1992, 48, 5691. (d) Rozema, M. J .; Sidduri,
A.; Knochel, P. J . Org. Chem. 1992, 57, 1956. (e) Hwang, C.-D.; Uang,
B.-J . Tetrahedron: Asymmetry 1998, 9, 3979. (f) Rozema, M. J .;
Eisenberg, C.; L u¨ tjens, H.; Ostwald, R.; Belyk, K.; Knochel, P.
Tetrahedron Lett. 1993, 34, 3115. (g) Brieden, W.; Ostwald, R.; Knochel,
P. Angew. Chem., Int. Ed. Engl. 1993, 32, 582. (h) L u¨ tjens, H.;
Nowotny, S.; Knochel, P. Tetrahedron Asymmetry 1995, 6, 2675. (i)
Zhang, X.; Guo, C. Tetrahedron Lett. 1995, 36, 4947. (j) Reddy, C. K.;
Knochel, P. Angew. Chem., Int. Ed. Engl. 1996, 35, 1700. (k) Qiu, J .;
Guo, C.; Zhang, X. J . Org. Chem. 1997, 62, 2665. (l) Guo, C.; Qui, J .;
Zhang, X.; Verdugo, D.; Larter, M. L.; Christie, R.; Kenney, P.; Walsh,
P. J . Tetrahedron 1997, 53, 4145. (m) Lutz, C.; Knochel, P. J . Org.
Chem. 1997, 62, 7895. (n) Pritchett, S.; Woodmansee, D. H.; Gantzel,
P.; Walsh, P. J . J . Am. Chem. Soc. 1998, 120, 6423.
made instead to reaction with an excess of O-methylhy-
droxylamine hydrochloride in a 1:1 methanol-pyridine
solvent system at the reflux temperature. These condi-
tions gave rise to a chromatographically separable mix-
ture of 4 and 5 (Scheme 1). The less polar major
constituent 4 was easily identified since the out,out
geometry conserves C
isomer could be detected.
However, equilibration between 4 and 5 was noted in
CDCl solution. On standing for two days at room
2
symmetry. None of the in,in
(
17) Reviews: (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833. (b)
Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49.
18) For example: (a) Itsuno, S.; Frechet, J . M. J . Org. Chem. 1987,
(
3
5
2, 4140. (b) Corey, E. J .; Hannon, F. J . Tetrahedron Lett. 1987, 28,
233, 5237. (c) Evans, D. A. Science 1988, 240, 420. (d) Kitamura, M.;
temperature, approximately 10% of 4 had undergone
conversion to 5. The behavior of 5 was more dramatic in
that isomerization to 4 was 90% complete. This isomer
distribution may well represent the equilibrium point.
Since the catalytic hydrogenation of the 4/5 mixture
over 10% palladium on charcoal did not proceed up to
5
Okada, S.; Suga, S.; Noyori, R. J . Am. Chem. Soc. 1989, 111, 4028. (e)
Ito, Y. N.; Ariza, X.; Beck, A. K.; Bohac, A.; Ganter, C.; Gawley, R. E.;
K u¨ hnle, F. N. M.; Tuleja, J .; Wang, Y. M.; Seebach, D. Helv. Chim.
Acta 1994, 77, 2071. (f) Tombo, G. M. R.; Didier, E.; Loubinoux, B.
Synlett 1990, 547. (g) Yamakawa, M.; Noyori, R. J . Am. Chem. Soc.
1
995, 117, 6327. (h) Vidal-Ferran, A.; Moyano, A.; Peric a` s, M. A.; Riera,
A. Tetrahedron Lett. 1997, 38, 8773. (i) Goldfuss, B.; Houk, K. N. J .
Org. Chem. 1998, 63, 8998.
1
000 psi, reduction was effected alternatively with the
2
2
(
19) Casey, C. P.; Whiteker, G. T.; Melville, M. G.; Petrovich, L. M.;
Gavney, J . A., J r.; Powell, D. R. J . Am. Chem. Soc. 1992, 114, 5535.
20) Interestingly, the water molecule in 3 resides on a 3-fold axis,
borane‚THF complex in diglyme. After 5 days at 110-
1
20 °C, the diamine was obtained in 83% yield. Its
(
and the three molecules that surround it appear to behave almost as
a calixarene.
(21) Morris, J . C. M.S. Thesis, The Ohio State University, 1997.

Enantiopure C
2
-Symmetric VERDI Disulfonamides
J . Org. Chem., Vol. 64, No. 21, 1999 7931
Ta ble 1. En a n tiom er ic Excesses Resu ltin g fr om th e Asym m etr ic Ad d ition of Dieth yla zin c to Sever a l Ald eh yd es a s
Ca ta lyzed by Disu lfon a m id es 7a -c in th e P r esen ce of Tita n iu m Isop r op oxid e
purification was most readily accomplished by crystal-
lization of the dihydrochloride salt 6.
The optimal conditions for preparing disulfonamides
(entries 4-6), in line with an anticipated dropoff in the
tightness with which the sulfonamide nitrogens bind to
the titanium center in the transition state. While satu-
rated cyclic (entries 13 and 14) and acyclic aldehydes
(entries 7 and 8, and 11 and 12) continue to provide
R-carbinols at a comparably high level of enantioselec-
tivity (88-98% ee), the presence of a conjugated double
bond brings on a 10-20% reduction in the level of
asymmetric induction. This decrease likely results from
the fact that the enforced coplanarity of the R- and
â-trigonal centers with the carbonyl π-bond causes the
two possible planar orientations to have diminished
energy differences once complexed. The least well-
behaved substrate of this family (entries 9 and 10 and
7
a and 7b involved the use of DMAP as the acid
scavenger. Ligand 7c was not obtained by comparable
reaction with triflyl chloride. Success was realized instead
with triflic anhydride and Hunig’s base, although the
yield was only modest.
Asym m etr ic Ca ta lysis. After a brief scan of reaction
2
3
conditions, those developed by Yoshioka were found to
be optimal and were therefore adopted. The results of
catalyzed diethylzinc additions to seven aldehydes are
compiled in Table 1. For all 16 entries, the level of 7 was
maintained constant at 0.01 equiv. For n-hexanal, cin-
1
5 and 16) is cinnamaldehyde. Although the aromatic
aldehydes share similar structural features, they appear
more capable of adjusting their geometry, perhaps with
some loss of conjugation, to better fit into the catalytic
complex for ethyl group transfer, which occurs predomi-
nantly to the Re face.
namaldehyde, and hydrocinnamaldehyde (entries 7-12),
somewhat lesser amounts of titanium isopropoxide and
more elevated proportions of diethylzinc led to modestly
improved chemical yields and are therefore cited. Without
exception, all three disulfonamides were seen to function
as efficient precatalysts for the formation of 8.
While high asymmetric induction (89-98% ee) was
observed with benzaldehyde (entries 1-3), the addition
of a 4-fluoro substituent decreased enantioselectivity
While the enantioselectivities are in most cases close
to those published earlier,16 the results with CH
3 2 4
(CH ) -
CHO seem to be better than those observed previ-
ously.1
4b,16k
Mech a n istic An a lysis. Studies by three other re-
search groups have an important bearing on the possible
means by which the VERDI disulfonamide catalysts
proceed to bring about titanium-mediated ethylzincation.
Ohno and co-workers established that these addition
reactions do not proceed at a reasonable rate when either
(
22) Brown, H. C.; Heim, P.; Yoon, N. M. J . Am. Chem. Soc. 1970,
9
2, 1637.
the disulfonamide or the titanium isopropoxide is
(
23) Nowotny, S.; Vettel, S.; Knochel, P. Tetrahedron Lett. 1994, 35,
6a-c
4
539.
omitted.1
Parallel studies with 7a -c in this laboratory

7
932 J . Org. Chem., Vol. 64, No. 21, 1999
Paquette and Zhou
Sch em e 2
ent migrates to an “apical” position. This option, which
would presumably result in ligation of titanium to the
oxygen lone pair as shown in 11 in order to minimize
steric congestion,27 offers improved π-facial discrimina-
tion relative to “apical” coordination of the aldehyde. Once
the ethyl group is transferred to the Re face with
generation of 12, further reaction with titanium isopro-
poxide establishes the catalytic cycle.
We emphasize that while the exact structures of the
active species are presently unclear, the working model
advanced in Scheme 2 provides reasonable mechanistic
insight. For the proposed mechanism, enantioselectivity
is determined during ethyl transfer from Ti to C in the
lower-energy complex 11. On the basis of the observed
results, it is possible to conclude that disulfonamides 7
are highly capable of generating a chiral environment
that usefully distinguishes the Re and Si faces of alde-
hydes. The unfavored interactions28 between the R group
of the aldehyde and the VERDI backbone in complex 13
render matters unfavorable for transfer of the ethyl group
to the Si face.
clearly demonstrated the existence of powerful catalytic
efficiency with these compounds.
Con clu sion s. The enantiopure VERDI disulfonamides
7 in combination with titanium isopropoxide and dieth-
ylzinc are effective chiral promoters for enantioselective
1,2 alkyl addition to structurally varied aldehydes. The
methodology is simple and operationally practical to
implement, requires no removal of liberated isopropyl
alcohol, and functions as a typical ligand-accelerated
In a somewhat later development, Knochel reported
that the realization of high enantioselectivities is de-
2
3
pendent on the nature of the titanium alkoxide. Ti(Oi-
Pr) and Ti(Ot-Bu) proved notably effective.
4
4
More recently, Walsh demonstrated that titanium
isopropoxide does not react directly with disulfonamides
to give bis(alkoxide) complexes.1 By making recourse
6n
28
catalytic process.
to the more reactive Ti(NMe)
2
(Oi-Pr)
2
reagent, they could
The VERDI ligand system, by virtue of its inherent
structural rigidity, sulfonamide spacing, and bite angle,
draws the metal center closer to the chirality. These
features may be at the heart of the very high selectivities.
The success realized with aliphatic aldehydes is of
particular interest. Investigations aimed at defining the
utility of other VERDI catalyst systems are expected to
be the subject of future reports.
obtain X-ray quality crystals, establish the tetradentate
nature of the ligand (coordination through the sulfona-
mide nitrogen and oxygen) so as to maintain a C -
2
symmetric environment, and demonstrate that these
complexes qualify potentially as the catalytically active
species.
In light of the well-established fact that dialkylzinc
reagents react with disulfonamides to generate the
expected complexes,24 we propose for consideration the
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under a
nitrogen or argon atmosphere. Melting points are uncorrected.
The column chromatographic separations were performed with
Woelm silica gel (230-400 mesh). Solvents were reagent grade
and in most cases dried prior to use. The purity of all
possibility that the first-formed intermediate is the zinc
complex to 7. Introduction of titanium isopropoxide can
be considered to allow for the intervention of an alkylti-
tanium species 10, quite possibly via the titanate complex
9
. To coordinate 10 to an aldehyde, for which ample
1
compounds was shown to be >95% by TLC and high field H
2
5,26
13
precedence exists,
we suggest that the ethyl substitu-
and C NMR. The high-resolution mass spectra were recorded
at The Ohio State University Campus Chemical Instrumenta-
tion Center. Elemental analyses were performed at Atlantic
Microlab, Inc. Norcross, GA.
(
24) (a) Imai, N.; Sakamoto, K.; Takahashi, H.; Kobayashi, S.
Tetrahedron Lett. 1994, 35, 7045. (b) Imai, N.; Takahashi, H.; Koba-
yashi, S. Chem. Lett. 1994, 177. (c) Denmark, S. E.; Nakajima, N.;
Nicaise, O. J .-C. J . Am. Chem. Soc. 1994, 116, 8797. (d) Denmark, S.
E.; Nakajima, N.; Nicaise, O. J .-C.; Faucher, A. M.; Edwards, J . P. J .
Org. Chem. 1995, 60, 4884. (e) Denmark, S. E.; Christenson, B. L.;
Coe, D. M.; O’Connor, S. P. Tetrahedron Lett. 1995, 36, 2215. (f)
Denmark, S. E.; Christenson, B. L.; O’Connor, S. P. Tetrahedron Lett.
(
1S,3R,6R,8S)-1,2,3,6,7,8-Hexah ydr o-2,2,7,7-tetr am eth yl-
1
,3:6,8-d im et h a n op h en a n t h r en e-4,5-d ion e (E,E)-Bis(O-
(26) (a) Reetz, M. T.; K u¨ kenh o¨ hner, T.; Weinig, R. Tetrahedron Lett.
1986, 27, 5711. (b) Reetz, M. T. Organotitanium Reagents in Organic
Synthesis; Springer-Verlag: Berlin, 1986.
(27) Reetz, M. T.; H u¨ llmann, M.; Massa, W.; Berger, S.; Rademacher,
P.; Heymanns, P. J . Am. Chem. Soc. 1986, 108, 2405.
(28) Berrisford, D. J .; Bolm, C.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1059.
1
6
995, 36, 2219. (g) Denmark, S. E.; O’Connor, S. P. J . Org. Chem. 1997,
2, 3390. (h) Denmark, S. E.; O’Connor, S. P.; Wilson, S. R. Angew.
Chem., Int. Ed. 1998, 37, 1149.
25) Weidmann, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1983,
2, 31.
(
2

Enantiopure C
2
-Symmetric VERDI Disulfonamides
J . Org. Chem., Vol. 64, No. 21, 1999 7933
m eth yloxim e) (4) an d (1S,3R,6R,8S)-1,2,3,6,7,8-Hexah ydr o-
,2,7,7-tetr a m eth yl-1,3:6,8-d im eth a n op h en a n th r en e-4,5-
d ion e (E,Z)-Bis(O-m eth yloxim e) (5). A solution of diketone
4.33 (d, J ) 9.4 Hz, 2 H), 3.22 (s, 6 H), 2.86 (m, 2 H), 2.75 (m,
2 H), 2.66 (m, 2 H), 1.44 (s, 6 H), 1.35 (d, J ) 9.7 H, 2 H), 0.86
2
(s, 6 H); 13C NMR (75 MHz, CDCl
) δ 146.6, 131.8, 126.0, 57.1,
3
1
0
+
2
(0.27 g, 0.92 mmol) and O-methyhydroxylamine hydrochlo-
ride (0.50 g, 6.0 mmol) in a mixture of pyridine (18 mL) and
methanol (18 mL) was refluxed overnight under N . Removal
48.5, 46.8, 43.4, 39.5, 34.5, 26.8, 23.9; HRMS (EI) m/z (M )
2
1
calcd 452.1804, obsd 452.1761; [R]
D
+35 (c 0.5, CHCl
3
). Anal.
2
Calcd for C22
H, 7.15.
H N O S : C, 58.38; H, 7.13. Found: C, 58.54;
32 2 4 2
of the volatiles afforded a white solid. After ample trituration
with hexanes/ethyl acetate (2:1), the combined solutions were
concentrated and chromatographed on silica gel. Elution with
the same solvent system afforded 226 mg of 4 and 58 mg of 5
N ,N ′-[(1S ,3R ,4S ,5S ,6R ,8S )-1,2,3,4,5,6,7,8-Oct a h yd r o-
2,2,7,7-t et r a m et h yl-1,3:6,8-d im et h a n op h en a n t h r en -4,5-
ylen e]bis[p-tolu en esu lfon a m id e] (7b). Reaction of 6 (25
mg, 0.068 mmol) with p-toluenesulfonyl chloride (32 mg, 0.17
mmol) and DMAP (120 mg, 0.098 mmol) in CH Cl (15 mL)
(
combined yield of 89%).
For 4: white solid, mp 57-58.5 °C; IR (KBr, cm-1) 1466,
2
2
1
1
3
5
050; H NMR (300 MHz, CDCl
3
) δ 6.81 (s, 2 H), 3.89 (s, 6 H),
under the predescribed conditions furnished 40 mg (89%) of
.82 (t, J ) 6.1 Hz, 2 H), 2.80 (t, J ) 5.3 Hz, 2 H), 2.69 (t, J )
.4 Hz, 1 H), 2.64 (t, J ) 5.4 Hz, 1 H), 1.63 (d, J ) 9.3 Hz, 2
7b as a white solid, mp 128 °C dec; IR (KBr, cm-1) 3311, 1599,
1
1342, 1160; H NMR (300 MHz, CDCl ) δ 7.86 (m, 4 H), 7.30
3
1
3
H), 1.48 (s, 6 H), 0.64 (s, 5 H); C NMR (75 MHz, CDCl
1
3
) δ
(m, 4 H), 6.70 (s, 2 H), 5.69 (dd, J ) 3.1, 8.4 Hz, 2 H), 4.52 (d,
J ) 8.5 Hz, 2 H), 2.58 (m, 2 H), 2.49 (m, 4 H), 2.43 (s, 6 H),
57.8, 146.7, 127.8, 126.0, 61.5, 50.0, 48.3, 42.9, 33.4, 26.2, 22.8;
+
21
13
HRMS (EI) m/z (M ) calcd 352.2151, obsd 352.2163; [R]
929 (c 0.417, C ).
Anal. Calcd for C22
D
1.27 (d, J ) 9.2 Hz, 2 H), 0.84 (s, 6 H), 0.52 (s, 6 H); C NMR
+
6
H
6
(75 MHz, CDCl ) δ 146.4, 142.8, 140.5, 131.8, 129.4, 127.3,
3
H
28
N
2
O
2
: C, 74.97; H, 8.01. Found: C,
125.5, 57.0, 48.1, 43.9, 38.7, 25.8 23.6, 21.4; HRMS (EI) m/z
7
4.85; H, 8.12.
(M
+
) calcd 604.2430, obsd 604.2450; [R]21 +186 (c 0.407,
D
For 5: white solid, mp 102-103.5°C; IR (KBr, cm-1) 1459,
CHCl ). Anal. Calcd for C H N O S : C, 67.52; H, 6.67.
3
34 40
2
4
2
1
1
248, 1065; H NMR (300 MHz, CDCl
3
) δ 6.87 (s, 2 H), 3.86
Found: C, 67.72; H, 6.73.
N ,N ′-[(1S ,3R ,4S ,5S ,6R ,8S )-1,2,3,4,5,6,7,8-Oct a h yd r o-
(s, 6 H), 3.73 (t, J ) 5.8 Hz, 1 H), 3.05 (t, J ) 0.6 Hz, 1 H),
2
3
1
5
.89-2.66 (m, 4 H), 1.70-1.61 (m, 2 H), 1.48 (s, 3 H), 1.46 (s,
H), 0.70 (s, 3 H), 0.57 (s, 3 H); C NMR (75 MHz, CDCl ) δ
59.4, 156.7, 146.7, 144.7, 131.7, 126.3, 125.2, 122.3, 61.6, 61.3,
0.6, 50.4, 49.4, 49.3, 48.8, 42.7, 35.2, 33.3, 26.7, 26.3, 22.9 (2
2
,2,7,7-t et r a m et h yl-1,3:6,8-d im et h a n op h en a n t h r en -4,5-
13
3
ylen e]bis[1,1,1-tr iflu or om eth a n esu lfon a m id e] (7c). To a
cold (-5 °C), magnetically stirred solution of 6 (150 mg, 0.41
mmol) and diisopropylethylamine (1.8 mL, 10.3 mmol) in CH -
2
+
21
C); HRMS (EI) m/z (M ) calcd 352.2151, obsd 352.2151; [R]
588 (c 0.64, C ). Anal. Calcd for C22 : C, 74.97; H,
.01. Found: C, 74.76; H, 8.07.
1S,3R,4S,5S,6R,8S)-1,2,3,4,5,6,7,8-Oct a h yd r o-2,2,7,7-
D
Cl (15 mL) was added triflic anhydride (138 µL, 0.82 mmol).
2
+
8
6
H
6
28 2 2
H N O
The reaction mixture was stirred at this temperature for 1 h,
allowed to warm to 20 °C for 1.5 h, diluted with 1 N HCl (50
mL), and agitated another 30 min before being extracted with
(
t e t r a m e t h yl-1,3:6,8-d im e t h a n op h e n a n t h r e n e -4,5-d ia -
m in e Dih yd r och lor id e (6). A clear solution of 4 (0.50 g, 1.4
mmol) in dry diglyme (150 mL) was cooled to 0 °C and treated
slowly with borane in THF solution (40 mL of 1 M, 40 mmol).
The reaction mixture was heated at 110-120 °C for 5 days,
cooled to 0 °C, treated cautiously with a solution of KOH (10
g) in water (70 mL), and reheated to 120 °C for 3 h. The
2 2
CH Cl . The combined organic phases were washed with water,
dried, and concentrated. Chromatography of the residue on
silica gel (elution with 5:1 hexanes/ethyl acetate) afforded 7c
-1
as a white solid (102 mg, 44%), mp 215 °C dec; IR (KBr, cm
)
1
3
5
215, 1438, 1368; H NMR (300 MHz, CDCl
3
) δ 6.88 (s, 2 H),
.58 (dd, J ) 2.4, 6.8 Hz, 2 H), 5.10 (d, J ) 6.9 Hz, 2 H), 2.70
(
m, 6 H), 1.43 (d, J ) 8.3 Hz, 2 H), 1.42 (s, 6 H), 0.76 (s, 6 H);
separated aqueous phase was extracted with CH
2
Cl
2
, and the
13
C NMR (75 MHz, CDCl
3
) δ 147.3, 130.1, 126.8, 57.5, 48.1,
signal not observed); HRMS
combined organic layers were treated with aqueous hydro-
chloric acid. The organic layer was removed, and the aqueous
4
5.8, 39.3, 34.1, 26.1, 23.3 (CF
3
+
21
(EI) m/z (M ) calcd 560.1238, obsd 560.1202; [R]
D
+141 (c
layer was extracted with CH
aqueous KOH solution. A fine white precipitate appeared. This
mixture was extracted with CH Cl , dried, and concentrated
to leave the diamine as an off-white solid (350 mg, 83%); H
NMR (300 MHz, CDCl ) δ 6.68 (s, 2 H), 4.71 (d, J ) 2.9 Hz, 1
H), 2.63 (m, 4 H), 2.34 (m, 2 H), 2.00 (s, 4 H), 1.40 (s, 6 H),
.36 (d, J ) 9.0 Hz, 2 H), 0.90 (s, 6 H); 13C NMR (75 MHz,
CDCl ) δ 144.7, 136.2, 124.3, 55.9, 50.8, 49.4, 38.9, 34.7, 26.9,
3.6; HRMS (EI) m/z (M ) calcd 296.2252, obsd 296.2271.
Reduction of 5 under parallel conditions afforded the di-
2 2
Cl in advance of basification with
0
.233, CHCl
.67. Found: C, 47.57; H, 4.82.
P r ototyp ica l En a n tioselective Ad d ition of Dieth ylzin c
to Ald eh yd es. In a dried, 100 mL Schlenk flask was placed a
0 mg (0.022 mmol) sample of 7a under argon. To this were
added degassed toluene (20 mL) and titanium isopropoxide
0.80 mL, 2.6 mmol), and the mixture was stirred at 40 to 50
C for 30 min prior to being cooled to -78 °C, at which point
3 26 6 2 4 2
). Anal. Calcd for C22H F N O S : C, 47.14; H,
4
2
2
1
3
1
1
(
°
3
+
2
a 1.0 M hexane solution of diethylzinc (3.0 mL, 3.0 mmol) was
introduced. The orange-colored solution was treated with
benzaldehyde (0.224 mL, 2.21 mmol), stirred at -40 °C for 16
h, and quenched with 2 N HCl (25 mL). The separated aqueous
phase was extracted with ether, and the combined organic
amine in a comparable yield.
Dry HCl gas was slowly introduced into an ethereal solution
of the diamine, the white solid was collected, and colorless
needles were obtained by recrystallization from methanol and
layers were washed with saturated NaHCO
and concentrated. Chromatography of the residue on silica gel
elution with 2:1 hexanes/ethyl acetate) gave 28 mg (93%) of
3
solution, dried,
-
1
1
ether; mp 252 °C; IR (KBr, cm ) 3448, 1597, 1518; H NMR
(
2
6
300 MHz, CDCl
3
) δ 7.01 (s, 2 H), 4.92 (d, J ) 3.6 Hz, 2 H),
(
.84 (m, 4 H), 2.74 (m, 2 H), 1.62 (d, J ) 9.6 Hz, 2 H), 1.52 (s,
21
the carbinol as a colorless oil (98% ee, [R]
CHCl )). In addition, 7a was recovered quantitatively. The
D
+43.9 (c 5.62,
+
H), 0.81 (s, 6 H) (NH
3
signals not seen); HRMS (EI) m/z
3
+
21
(M
- 2HCl) calcd 296.2252, obsd 296.2271; [R]
D
+162 (c 0.5,
enantiomeric purity of the product was determined by chiral
HPLC analysis on Daicel columns.
CH
8
3
OH). Anal. Calcd for C20 ‚CH OH: C, 62.83; H,
H
30Cl
2
O
2
3
.54. Found: C, 62.48; H, 8.39.
For these determinations, racemic carbinols were first
generated by the titanium isopropoxide-promoted addition of
diethylzinc to the several aldehydes at room temperature. This
uncatalyzed reaction does not proceed at a measurable rate
at -40 °C. The absolute configurations of the products were
N ,N ′-[(1S ,3R ,4S ,5S ,6R ,8S )-1,2,3,4,5,6,7,8-Oct a h yd r o-
2
,2,7,7-t et r a m et h yl-1,3:6,8-d im et h a n op h en a n t h r en -4,5-
ylen e]bis[m eth a n esu lfon a m id e] (7a ). A solution of 6 (120
mg, 0.325 mmol) and DMAP (400 mg, 3.27 mmol) in CH Cl
45 mL) was treated with methanesulfonyl chloride (60 µL,
2
2
(
derived by comparison of optical rotation data with literature
0
.78 mmol). After the reaction mixture had been stirred for 5
values.1
6b,23
Some of the alcohols were converted to their
h, 50 mL of 1 N hydrochloric acid was introduced. Thirty
minutes later, the product was extracted into CH Cl , and the
benzoate derivatives in order to allow UV detection by the
HPLC. The relevant data are contained in Tables 2 and 3.
2
2
combined organic phases were washed with water, dried, and
concentrated to leave 135 mg (90%) of 7a as a white solid, mp
1
95 °C dec; IR (KBr, cm-1) 3381, 1405, 1146; H NMR (300
1
Ack n ow led gm en t. Appreciation is extended to the
MHz, CDCl
3
) δ 6.80 (s, 2 H), 5.47 (dd, J ) 3.4, 9.3 Hz, 2 H),
donors of the Petroleum Research Fund, administered

7
934 J . Org. Chem., Vol. 64, No. 21, 1999
Paquette and Zhou
Ta ble 2. Op tica l Rota tion Da ta for Ca r bin ols 8 ([r]21D in CHCl3 Solu tion
Ta ble 3. Ch ir a l HP LC An a lysis Con d ition s (Da icel Colu m n s)
by the American Chemical Society, for partial support
of this research. We also extend our thanks to Prof.
Robin Rogers for the X-ray analysis and to Dr. Kurt
Loening for assistance with nomenclature.
dinates for 3. The authors have deposited the atomic coordi-
nates for the X-ray structures with the Cambridge Crystallo-
graphic Data Centre. The coordinates can be obtained, on
request, from the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, UK. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Su p p or tin g In for m a tion Ava ila ble: Tables giving the
crystal data and structure refinement information, bond
lengths and bond angles, torsion angles, atomic and hydrogen
coordinates, and isotropic and anisotropic displacement coor-
J O990984E