Practical synthesis of spirocyclic bis-C,C-glycosides. Mechanistic models in explanation of rearrangement stereoselectivity and the bifurcation of reaction pathways

Article abstract of DOI:10.1021/jo962020i

The susceptibility of glycal-derived carbinols to acid-catalyzed ring expansion is described. In the systems prepared from cyclopentanone, Ferrier ionization precedes the pinacol-like Wagner-Meerwein shift, thermodynamic control operates, and high stereoselectivity is seen if a C(6) substituent is present. In contrast, the adducts to cyclobutanone exhibit release of ring strain under kinetically controlled conditions and intercept the oxonium species reversibly formed via direct proton transfer. The results show that the substituents positioned on the glycal ring have a pronounced influence on whether a chair-like or twist-boat transition state geometry is adopted primarily. The composite reaction profiles reveal for the first time the fundamental importance of exothermicity and of substitution in these spiro glycosidation reactions. Since optical activity is preserved in all instances, the utility of this chemistry for the synthesis of bis-C,C-glycosides and more complex oxacyclics appears promising.

Full text of DOI:10.1021/jo962020i

J . Org. Chem. 1997, 62, 1713-1722
1713
P r a ctica l Syn th esis of Sp ir ocyclic Bis-C,C-glycosid es. Mech a n istic
Mod els in Exp la n a tion of Rea r r a n gem en t Ster eoselectivity a n d
th e Bifu r ca tion of Rea ction P a th w a ys
Leo A. Paquette,* Margaret J . Kinney, and Uta Dullweber
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received October 29, 1996X
The susceptibility of glycal-derived carbinols to acid-catalyzed ring expansion is described. In the
systems prepared from cyclopentanone, Ferrier ionization precedes the pinacol-like Wagner-
Meerwein shift, thermodynamic control operates, and high stereoselectivity is seen if a C(6)
substituent is present. In contrast, the adducts to cyclobutanone exhibit release of ring strain
under kinetically controlled conditions and intercept the oxonium species reversibly formed via
direct proton transfer. The results show that the substituents positioned on the glycal ring have
a pronounced influence on whether a chair-like or twist-boat transition state geometry is adopted
primarily. The composite reaction profiles reveal for the first time the fundamental importance of
exothermicity and of substitution in these spiro glycosidation reactions. Since optical activity is
preserved in all instances, the utility of this chemistry for the synthesis of bis-C,C-glycosides and
more complex oxacyclics appears promising.
The field of carbohydrate chemistry has witnessed
remarkable growth in recent times as a consequence of
intense interest in the synthesis of C-glycosides. The
discovery of biologically active members of this important
class of sugars in nature has resulted in the development
of many methods for their stereoselective construction.1
Particularly noteworthy is the wide range of approaches
which have proven serviceable. These extend from the
utilization of both electrophilic and nucleophilic carbo-
hydrates to the adoption of free radical techniques, Wittig
olefinations, palladium-mediated couplings, and con-
certed processes. Notwithstanding these advances, spi-
rocyclic bis-C,C-glycosides have not found similar favor.
Only in connection with the recent independent discover-
ies by Descotes2 and by Vasella3 of the feasibility of
preparing anomeric carbenes have reports of the capture
of these reactive intermediates with olefins to give
cyclopropanes made their appearance.
ion. Under conditions where the starting carbinols would
be derived from glycals and would therefore be enantio-
merically pure, this transformation would provide a
convenient means for establishing the absolute configu-
ration of a fully substituted carbon while delivering bis-
C,C-glycosides. Presented here are the results of an
extended study involving a variety of carbohydrate-based
glycals substituted in diverse ways. A preliminary
investigation5 had previously uncovered divergent re-
sponses from systems amenable to operation of the
Ferrier rearrangement.6 These variances provided im-
portant insight with regard to the ranking of competing
reactions available to six-membered oxonium ions and,
accordingly, have been evaluated more extensively. The
purpose of the present study was to develop an integrated
mechanistic model for these utilitarian processes.
Recent work in these laboratories has illustrated that
the acid-catalyzed rearrangement of dihydropyranyl-
carbinols such as 1 to spirocyclic ketones can be highly
diastereoselective.4 This efficient process results in the
generation of a new stereogenic center by means of
controlled pinacol-like 1,2-migration to a cyclic oxonium
Discu ssion a n d Resu lts
Scop e of th e In vestiga tion . Glyca l Syn th esis a n d
Cou p lin g. The structural features of glycals 2-8 were
considered to be sufficiently diverse for our purposes. The
complications associated with the C-1 lithiation of 3,4,6-
tris-O-(tert-butyldimethylsilyl)-D-glucal7 can be effectively
skirted by making recourse instead to the TIPS deriva-
tive. Although the utilization of 2 is no longer ac-
companied by R-silyl deprotonation,8 an excess of tert-
butyllithium is still required9 in order to realize efficient
lithiation in advance of condensation with cyclobutanone
and cyclopentanone to give 10 (78%) and 11 (96%),
respectively. A comparable procedure could be easily
applied to the acquisition of 12 and 13.
X Abstract published in Advance ACS Abstracts, March 15, 1997.
(1) (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545. (b) Levy, D.
E.; Tang, C. The Chemistry of C-Glycosides, Elsevier Science Inc.: New
York, 1995. (c) Postema, M. H. D. C-Glycoside Synthesis; CRC Press:
Boca Raton, FL, 1995.
(2) (a) Praly, J .-P.; El-Kharraf, Z.; Descotes, G. J . Chem. Soc., Chem.
Commun. 1990, 431. (b) Praly, J .-P.; El-Kharraf, Z.; Descotes, G.
Tetrahedron Lett. 1990, 31, 4441.
(3) (a) Briner, K.; Vasella, A. Helv. Chim. Acta 1989, 72, 1371. (b)
Vasella, A.; Uhlmann, P.; Waldraff, C. A. A.; Diederich, F.; Thilgen,
C. Angew. Chem., Int. Ed. Engl. 1992, 31, 1388.
(4) Paquette, L. A.; Lanter, J . C.; J ohnston, J . N. J . Org. Chem. 1997,
62, 1702.
(5) Paquette, L. A.; Dullweber, U.; Cowgill, L. D. Tetrahedron Lett.
1993, 34, 8019.
(6) (a) Ferrier, R. J . J . Chem. Soc. 1964, 5443. (b) Ferrier, R. J .;
Prasad, N. J . Chem. Soc. C 1969, 570.
(7) (a) Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E. J . Chem. Soc.,
Chem. Commun. 1986, 925. (b) Hanessian, S.; Martin, M.; Desai, R.
C. J . Chem. Soc., Chem. Commun. 1986, 926. (c) Lesimple, P.; Beau,
J .-M.; J aurand, G.; Sinay¨, P. Tetrahedron Lett. 1986, 27, 6201. (d)
Paquette, L. A.; Oplinger, J . A. Tetrahedron 1989, 45, 107. (e) Friesen,
R. W.; Sturino, C. F. J . Org. Chem. 1990, 55, 2572.
The efficacy with which 3,4-di-O-acetyl-L-rhamnal
responds to Ferrier rearrangement when treated with
(8) (a) Friesen, R. W.; Sturino, C. F.; Daljeet, A. K.; Kolaczweska,
A. J . Org. Chem. 1991, 56, 1944. (b) Friesen, R. W.; Trimble, L. A. J .
Org. Chem. 1996, 61, 1165.
(9) Boeckman, R. K., J r.; Bruza, K. J . Tetrahedron Lett. 1977, 4187.
S0022-3263(96)02020-8 CCC: $14.00 © 1997 American Chemical Society

1714 J . Org. Chem., Vol. 62, No. 6, 1997
Paquette et al.
Sch em e 1
has been observed previously in the case of the bis-TBS
ether of L-fucal.14
Glycal 8 was prepared comparably from L-fucal diac-
etate.11,12 The presence of two TBS groups in 8 did not
impede C-1 lithiation, as evidenced by the obtention of
22 and 23 in 77% and 83% yields, respectively.
boron trifluoride etherate and methanol in acetonitrile,
and the regioselectivity with which the resulting pseudo-
glycal undergoes hydride reduction,10 proved highly at-
tractive as a route to 3-deoxy-L-rhamnal, silylation of
which gave 4 (94%). The subsequent conversion of 4 into
15 by means of tert-butyllithium in THF proceeded in
72% yield. The competing self-aldol condensation of
cyclopentanone hampered purification, such that 15 could
be isolated in a pure state only after several chromatog-
raphies. No such difficulties were encountered during
the synthesis of 14, which was available by analogous
means in 65% yield.
In our hands, the preferable route to the bissilylated
D-xylal 5 consisted of the conversion of D-xylose into the
triacetoxyglycosyl chloride by exposure to zinc chloride
in acetyl chloride11 followed by reductive elimination with
chromium(II) acetate.12 This route is less labor intensive
than that involving the glycosyl bromide,13 an intermedi-
ate much more prone to spontaneous hydrolysis and
decomposition. With TIPS protection, the conversion of
5 to 16 (87%) and 17 (85%) proved uneventful. Entirely
analogous considerations dictated our preparation of 6
from D-arabinose via the chloride12 and not the bromide.13
When treated with excess TIPSCl or TIPSOTf, D-
galactal13 underwent silylation to give 9. Further heating
did not lead to protection of all three hydroxyl groups
for steric reasons. A decrease in size to the TBS level did
Releva n t Mech a n istic F ea tu r es. It has been known
that glycals function well as glycosyl acceptors once
activation has been accomplished with a suitable elec-
trophilic reagent. We wished to exploit the use of a
proton for this purpose. Since anhydrous conditions were
mandated in order to circumvent simple hydration
processes, recourse has been made throughout to the use
of camphorsulfonic acid as a catalyst and dry dichlo-
romethane as the solvent of choice. In those glycals
substituted with a potential leaving group in the allylic
C(4) position, there exists the possibility for operation of
a process other than direct conversion to intermediate B
(Scheme 1). The vulnerability of these systems for
possible competing generation of more highly conjugated
oxonium ions of type C could set the stage for the
operation of a second rearrangement pathway.
It is well at this point to recognize that while the
generation of B qualifies as a potentially reversible
process, formation of C is essentially irreversible. An-
other distinction between these intermediates resides in
their electrophilic character. In B, the positive charge
is constrained to reside on two conjoined atoms and must
(14) Horton, D.; Priebe, W.; Varela, O. Carbohydr. Res. 1985, 144,
325 and references cited therein.
(15) Relevant examples include the following. (a) Danishefsky, S.;
Kerwin, J . F., J r. J . Org. Chem. 1982, 47, 3803. (b) Danishefsky, S.;
Kato, N.; Askin, D.; Kerwin, J . F., J r. J . Am. Chem. Soc. 1982, 104,
360. (c) Wittman, M. D.; Halcomb, R. L.; Danishefsky, S. J .; Golik, J .;
Vyas, D. J . Org. Chem. 1990, 55, 1979. (d) Dawe, R. D.; Fraser-Reid,
B. J . Chem. Soc., Chem. Commun. 1981, 1180. (e) Tsukiyama, T.;
Isobe, M. Tetrahedron Lett. 1992, 33, 7911. (f) Tsukiyama, T.; Peters,
S. C.; Isobe, M. Synlett 1993, 413. (g) Valverde, S.; Garcia-Ochoa, S.;
Martin-Lomas, M. J . Chem. Soc., Chem. Commun. 1987, 383. (h)
Borowiecka, J .; Lipka, P.; Michalska, M. Tetrahedron 1988, 44, 2067.
(i) Frappa, I.; Sinou, D. Synth. Commun. 1995, 25, 2941. (j) Pe´rez-
Pe´rez, M.-J .; Doboszewski, B.; Rozenski, J .; Herdewijn, P. Tetrahedron:
Asymmetry 1995, 6, 973. (k) Banik, B. K.; Manhas, M. S.; Bose, A. K.
J . Org. Chem. 1994, 59, 4714. (l) Booma, C.; Balasubramanian, K. K.
Tetrahedron Lett. 1993, 34, 6757. (m) Booma, C.; Balasubramanian,
K. K. J . Chem. Soc., Chem. Commun. 1993, 1394. (n) Nakata, M.;
Tamai, T.; Miura, Y.; Kinoshita, M.; Tatsuta, K. J . Antibiot. 1993, 46,
813. (o) Paterson, I.; Smith, J . D.; Ward, R. A. Tetrahedron 1995, 51,
9413. (p) Noshita, T.; Sugiyama, T.; Kitazumi, Y.; Oritani, T.
Tetrahedron Lett. 1994, 35, 8259. (q) Lo´pez, J . C.; Go´mez, A. M.;
Valverde, S.; Fraser-Reid, B. J . Org. Chem. 1995, 60, 3851. (r) Lo´pez,
J . C.; Fraser-Reid, B. J . Chem. Soc., Chem. Commun. 1992, 94. (s)
Fraser-Reid, Tsang, R. Strategies and Tactics in Organic Synthesis;
Academic Press Inc.: New York, 1989.
permit advance to 7 to be made. However, the final
capping proceeded very slowly and some intramolecular
silyl transfer was noted. A related silyl group migration
(10) Martin, A.; Pais, M.; Monneret, C. Carbohydr. Res. 1983, 113,
21.
(11) (a) Brauns, D. H. J . Am. Chem. Soc. 1924, 46, 1484. (b) Hudson,
C. S.; J ohnson, J . M. J . Am. Chem. Soc. 1915, 37, 2748. See also: (c)
Vercellotti, J . R.; Egan, L. P.; Squires, T. G. Carbohydrate Res. 1970,
14, 263 and references cited therein.
(12) (a) Pollon, J . H. P.; Llewellyn, G.; Williams, J . M. Synthesis
1989, 758. (b) Corey, E. J .; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron
Lett. 1981, 22, 3455.
(13) (a) Weygand, F. Methods Carbohydr. Chem. 1 1962, 182. (b)
Humoller, F. L. Methods Carbohydr. Chem. 1962, 1, 83. (c) Pigman,
W.; Roth, W. Methods Carbohydr. Chem. 1963, 2, 405.

Practical Synthesis of Spirocyclic Bis-C,C-Glycosides
J . Org. Chem., Vol. 62, No. 6, 1997 1715
Ta ble 1. Acid -Ca ta lyzed Isom er iza tion in Ta n d em w ith th e F er r ier Rea r r a n gem en t (CSA, CH2Cl2, r t)
therefore be regarded as relatively dense. The greater
degree of delocalization available to C can only serve to
render its cationic character more diffuse.
(viz. A f C f E), kinetically attractive in a great many
circumstances because of the stabilization inherent to
C,15 might not be overridden in favor the A f B f D
pathway by proper selection of the cyclic carbinol unit.
Indeed, the longer lifetime enjoyed by C because of its
enhanced thermodynamic stability allows such interme-
diates to be trapped by less strained neighboring cyclo-
pentanol units.
Op er a tion of th e F er r ier Rea r r a n gem en t. The
first carbinol observed to follow the A f C f E reaction
channel was 11 (Table 1). During the course of 1 h, its
smooth conversion exclusively into the enantiopure ke-
tone 24 could be conveniently monitored by TLC analysis.
The stereochemistry assigned to this product followed
straightforwardly from NOE measurements (see F ).
Comparable unidirectionality was exhibited by 13, which
was transformed rather more slowly (30 h) into 25 (81%
isolated). The absolute configuration of the spirocyclic
The connectivity between the electrophilicity of the
oxonium ion and ensuing pinacol-like rearrangement is
multifaceted. Established elsewhere is the fact that
simple substitution of the dihydropyran ring with one or
two alkyl groups engenders sufficient inductive electron
donation to reduce the potential for isomerization sig-
nificantly.4 Only cyclobutanol derivatives undergo ring
expansion at a rate to be synthetically useful. We
expected that the presence of electronegative oxygen
substituents, so plentiful in carbohydrates of virtually
all types, would reverse this effect and allow for the ring
expansion of cyclopentanol derivatives as well. As will
be seen, this has proven to be so.
Beyond this, we became specifically interested in
determining whether the Ferrier rearrangement option

1716 J . Org. Chem., Vol. 62, No. 6, 1997
Paquette et al.
carbon in 25 was unequivocally established on the basis
of COSY and NOE experiments (see G). In addition, the
tentative assignments was derived from several 2-D
1
NMR experiments. Following assignment of all H and
1
13C signals by means of H-1H COSY 90 and 1H-13C
phase-sensitive correlation measurements, a long-range
semiselective DEPT study in which H(2)ax was irradiated
revealed strong enhancements of C(6), as well as C(1),
C(3), and C(4) (see H). The intense response of C(6) is
especially reinforcing of the earlier belief that the car-
bonyl center is oriented axially. Hence, the configuration
of the spiro carbon (C(1)) in 29 is necessarily S.
Substrates 11 and 13, which have their X and Y
substituents trans-disposed at the Ferrier oxonium step
(C), undergo ring expansion readily. Should 21 and 23
react similarly, the X/Y relationship in C would be cisoid.
downfield shifting of H(8)ax and H(10)ax brought on by
their 1,3-diaxial relationship to the ether oxygen allowed
for the definition of H(11)eq and recognition of its proxim-
ity to the pyranyl proton shown. At this juncture, it was
of more than passing interest that both 11 and 13 had
responded to the intervention of C by migrating a
methylene carbon to the axial surface of the pyran ring.
A more detailed consideration of this significant issue is
presented below.
By contrast, diastereofacial selectivity was almost
totally eroded during the ring enlargement of 17. Al-
though the time required for complete consumption of
this carbinol was short (2 h), irreversible conversion to a
chromatographically inseparable 1.1:1 mixture of 26 and
27 materialized. Accordingly, an oxonium ion (C) car-
rying only the X substituent loses essentially all capabil-
ity for controlling the stereoselectivity of the ring expan-
sion. On this basis, the functional group Y, when present
in tandem with and trans to X, is recognized to have
broad impact on setting the configuration of the incipient
spirocyclic center.
This conclusion receives additional support from 16,
the only cyclobutanol of the seven examined herein to
be predisposed to the Ferrier process to some degree. In
this instance, a 1.2:1 mixture of epimers 28 was produced
in addition to 29 (58%) and 30 (2%). As in the preceding
example, the Ferrier intermediate was inadequately
substituted to engender desirable stereochemical control.
The was not the case for direct ring expansion along the
A f B f D reaction channel. The combined effect of
the OR and X substituents resident in the intermediary
oxonium species is to control migratory selectivity to the
appealing extent of 30:1.
However, neither glycal experienced rearrangement over
a prolonged period of time. Rather, adventitious mois-
ture was incorporated to deliver the hydrated products
45 and 46, respectively. An interesting reactivity profile
had now been delineated.
Con sequ en ces of Rin g Str a in Relief. Of the several
butanols prepared, only 14 is structurally unable to
undergo the Ferrier rearrangement (Table 2, experiment
8). In the event, the response of 14 to acid-catalyzed
isomerization was to deliver the (S)-configured spirocyclic
ketone 37 four times more prevalently than the R
diastereomer 38. Only 16 (experiment 4) and 22 (experi-
ment 11) subsequently proved stereoselective in the same
direction. In the case of 16, the bias for the S product
proved to be the most accentuated (30:1). In the other
four examples surveyed (10, 12, 14, and 18), the domi-
nant bicyclic ketone product was R-configured at the
spirocyclic carbon atom. The detailed structural features
of each bis-C,C-spiro glycoside were unequivocally es-
tablished by spectroscopic methods of the type previously
noted, with selected details provided in the Experimental
Section. The highly crystalline nature of 37 allowed for
its structural corroboration by crystallographic means
(Figure 1).
The stereochemical definition of 29 and 30 began by
comparing the chemical shift data of several protons. The
appearance of H(3) and H(5)ax in 29 at positions farther
downfield than those in 30 is indicative of their spatial
proximity to an axially disposed carbonyl group. Likewise
No hint of even very modest operation of the Ferrier
rearrangement could be uncovered in experiments 6, 7,
and 9-11. These findings strongly implicate the opera-
tion of kinetic control during non-Ferrier ring expansion.
According to this hypothesis, proton transfer to the
dihydropyranyl carbinol A to generate the oxonium ion
B in Scheme 1 occurs quite readily. The strain release
associated with the ring expansion of a cyclobutanol
causes B to be intercepted with only minimal energetic
costs. The exothermicity associated with the conversion
of B to D under these circumstances is likely mirrored
to a large extent in the associated transition state.
When less reactive cyclopentanol derivatives are in-
volved, oxonium ions of type B are not comparably
H(4), H(5)eq, and H(2)ax in 30 are deshielded by an
equatorially oriented carbonyl. This phenomenon has
been widely observed in this study. Confirmation of the

Practical Synthesis of Spirocyclic Bis-C,C-Glycosides
J . Org. Chem., Vol. 62, No. 6, 1997 1717
Ta ble 2. Sp ir ocyclic Bis-C,C-glycosid e F or m a tion via Dir ect Rin g Exp a n sion (CSA, CH2Cl2, r t)
consumed in the reaction manifold which results in the
production of D. As a consequence, time is available for
B to revert to A, which more slowly generates the more
stable cationic intermediate C. Once formed, species C
is much longer lived since it cannot return to A and
ultimately proceeds forward to generate E. From this
perspective, the Ferrier alternative is viewed to be the
thermodynamic option. On the basis of the experimental
data, we conclude that the rate of formation of B must
be considerably faster than that of C. Beyond this, the
Ferrier process is observed uniquely because little energy
advantage accrues to the Wagner-Meerwein shift of a
cyclopentanol in B to a cyclohexanone in D. Not only is
ring strain presumed to be closely comparable in B and
D but the trade-off of an oxonium ion for a carbonyl group
may well be virtually isoenergetic.
standard conditions, this carbinol gave rise to a multi-
component product mixture reflected by at least seven
different spots on TLC. The characterization of these
substances was not pursued.
Ster eoch em ica l Con sid er a tion s. The mechanistic
model advanced to this point has not yet specifically
addressed the very pertinent issue of stereochemistry.
For the thermodynamic pathway which eventuates in the
formation of Ferrier products, it is clear that a trans-
disposed C-5/C-6 substituent pair is conducive to high-
level control of π-facial stereoselectivity in the migratory
A remaining consideration is the anomalous behavior
of 15. When exposed to camphorsulfonic acid under the

1718 J . Org. Chem., Vol. 62, No. 6, 1997
Paquette et al.
Sch em e 2
step. Upon inspection of conformations I and J , derived
formally by appropriate ionization of 11 and 13, respec-
tively, the expectation is that the substituents positioned
at C-5 and C-6 will act in tandem to demand concomitant
projection into equatorial domains. The associated mini-
mization of nonbonded steric interactions will cause the
illustrated, stereochemically enantiomeric conformations
to be dominant. Stereoinduction will subsequently be
manifested because of the advantages available to the
development of chair-like (rather than twist-boat) char-
acteristics in the transition state to product. For I, this
guarantees that the spirocyclic carbon will eventuate as
S in 24. The change in configuration at the stereogenic
centers in J will reverse the orientation of the pyran ring
(as shown) and force a preference for genesrating the
spirocyclic carbon in the R series. The substantial dropoff
in stereoselectivity exhibited by 16, 17, and 19 (Table 1)
can be explained in terms of reduced rigidity within the
relevant oxonium ion conformations.
In the latter instance, the customarily preferred mode
of addition, i.e., M f 47, is impeded by the steric bulk of
the neighboring substituent, such that antiperiplanar
attack to give 48 operates instead.
To gain a comparable appreciation of the stereoselec-
tivity of the direct ring expansion reactions requires a
more detailed analysis of reaction exothermicity. It is
reasonable to assume, since cyclobutanol 16 reacts in part
via the Ferrier pathway, that it is the least reactive
member of this subset of carbinols. A direct consequence
of this scenario is the likelihood that the enhanced
reaction enthalpy should be accompanied by heightened
discrimination between the two diastereomeric transition
states. Following the generation of the oxonium ion,
conformation K will be adopted because of the diequa-
torial orientation of both pendant groups. Of the two
stereocontrolled 1,2-shifts available to K, the experimen-
tal data reveal that pathway a leading via the twist-boat
arrangement L to 29 dominates significantly (30:1) over
the chair-like alternative which leads directly to 30
(Scheme 2). This ordering of events is viewed as plau-
sible if the transition states are late and resemble the
spirocyclic ketones. Under these circumstances, pathway
a and the involvement of L serves to lessen the mutual
repulsive interaction16 of the very large OTIPS groups,
a condition which persists in 30. Our anticipation of a
lower enthalpy content for L is supported by precedent.
For example, trans-1,2-di-tert-butylcyclohexane prefers
to exist in the boat form rather than either of the chair
options because maximum relief from steric interactions
is thereby realized.17 Also, unlike the bromination of
4-tert-butylcyclohexene which proceeds with a greater
than 94:6 preference for diaxial addition, the 3-tert-butyl
isomer gives predominantly the diequatorial dibromide.18
A parallel situation, but with sterically less demanding
substituents, is present in 12 as reflected in N. Although
the level of nonbonded interaction between the groups
is somewhat reduced, a kinetic predisposition for ring
expansion via a twist-boat persists to the 4.6:1 level.
The energetics of two ring expansion pathways are
seen to be capable of reversal with modest structural
modifications. Removal of the 4-OTBS substituent in N
(from 12) as in O (from 14) is a case in point. The
response exhibited by O is to proceed to produce prefer-
entially (4.7:1) via the chair-like transition state alterna-
tive. Evidently, the two diequatorial substituents resid-
(17) (a) van de Graaf, G.; van Bekkum, H.; van Konigsveld, H.;
Sinnema, A.; van Veen, A.; Wepster, B. M.; van Wijk, A. M. Recl. Trav.
Chim. Pays-Bas 1974, 93, 135. (b) van de Graaf, B.; van Bekkum, H.;
Wepster, B. M. Recl. Trav. Chim. Pays-Bas 1978, 97, 268.
(18) Barili, P. L.; Bellucci, G.; Marioni, F.; Morelli, I.; Scartoni, V.
J . Org. Chem. 1972, 37, 4353.
(16) (a) Cieplak, P.; Howard, A. E.; Powers, J . P.; Rychnovsky, S.
D.; Kollman, P. A. J . Org. Chem. 1996, 61, 3662. (b) Rychnovsky, S.
D.; Yang, G.; Powers, J . P. J . Org. Chem. 1993, 58, 5251. (c)
Rychnovsky, S. D.; Skalitsky, D. J . Tetrahedron Lett. 1990, 31, 945.

Practical Synthesis of Spirocyclic Bis-C,C-Glycosides
J . Org. Chem., Vol. 62, No. 6, 1997 1719
ing in O are insufficiently bulky to play a comparable
controlling role.
the latter alternative must encounter a 1,3-diaxial in-
teraction with an OTIPS group.
The fundamental importance of exothermicity in acid-
catalyzed pinacol-like Wagner-Meerwein rearrange-
ments of glycal-derived systems has been clearly dem-
onstrated. The cyclobutanol systems rapidly isomerize
directly in high yield under kinetically controlled condi-
tions. When cyclopentanols are involved, the prior onset
of the Ferrier rearrangement is necessary for ring expan-
sion to occur. The stereoselectivity of these slower,
thermodynamically controlled processes can be very high,
particularly when the C(6) position is substituted. In-
terestingly, the direction of stereoinduction in the same
carbohydrate series is sometimes reversed as the pendant
ring is altered in size from 4- to 5-membered. The
rhamnal derivatives 12 and 13 are exemplary. Whereas
12 isomerizes to give predominantly 35 in which the new
bond is equatorial, 13 is transformed exclusively into 25
which has its new bond axially disposed.
The definitive consequence of the extent of substitution
and the stereochemical orientation of these groups on the
favored reaction pathway is reflected also in the rear-
rangements of 10 and 20. These isomeric glycals are
almost identically substituted, but differ in the configu-
ration of C(5). In the derived oxonium ions, this OSiR3
is either equatorially disposed as in P or projected axially
as in Q. Notwithstanding, both intermediates marginally
favor isomerization by way of a chair-like geometry. The
bias exhibited by P is the opposite of that found in K,
presumably because P (and Q as well) is more reactive
and faces an earlier transition state. In addition, entry
into the twist-boat manifold is met with the onset of 1,3-
pseudodiaxial interaction involving the CH2OTIPS group.
When the C(5) substituent is positioned axially as it is
for 20 (see Q) and 22 (see R), there exists an added steric
deterrent to ring expansion via a twist-boat arrangement
in the form of a developing 1,3-diaxial-like interaction.
Since this pathway is not completely curtailed, it is
entirely possible that our depictions of the oxonium ion
intermediates are too chair-like. This issue is brought
home in a more obvious manner when the stereoselection
exhibited by 18 is scrutinized. The two axial/equatorial
The scope and mechanism of these reactions have been
investigated in sufficient detail to provide clear guidance
that nonbonded steric interactions between substituents
on the pyran ring have considerable influence on the
stereoselectivity of the Wagner-Meerwein shift. The
formation of axially-substituted glycosides as the custom-
ary end products of Ferrier rearrangements is widely
recognized.6,15b Similarly, the formation of R-glycosides
is favored in nucleophilic additions to unsaturated sugar
derivatives.19 The dominance of axial attack has usually
been attributed to the energy differences of the half-chair
and half-boat transition states, but without serious
consideration of global substitution.7a The kinetic ano-
meric effect has been noted to be overridden by steric
effects in certain cases.12,21 The accompanying paper4
provides some indication of the impact of customary
stereoelectronic control on the pinacol rearrangement in
the absence of these secondary effects.
The current investigation makes apparent for the first
time the potential of reaction sequences in which a glycal
is deployed to serve as both the initiator and termination
point of a pinacol rearrangement. Some indication of the
richness of the chemistry made possible by these trans-
formations is reflected in the Baeyer-Villiger oxidation
of 35 to furnish the spiro acetal 49. The development of
further useful conversions founded on this concept is the
object of ongoing studies.22
disubstituted chair-like oxonium ion conformations theo-
retically available to this species are S and T. Although
the formation of 39 is favored, there exists no clear
indication whether this spiro glycoside arises by passage
of S through a twist-boat geometry or by the direct
advancement of T to a chair-like conformer. Note that
(19) Kennedy, J . F. Carbohydrate Chemistry; Oxford Science Pub-
lications: Clarendon Press: Oxford, England, 1988.
(20) Kaila, N.; Blumenstein, M.; Bielawska, H.; Franck, R. W. J .
Org. Chem. 1992, 57, 4576.
(21) Kirby, A. J . The Anomeric Effect and Related Stereoelectronic
Effects at Oxygen; Springer Verlag: New York, 1983.

1720 J . Org. Chem., Vol. 62, No. 6, 1997
Paquette et al.
1 H), 2.25-2.16 (m, 2 H), 1.90-1.76 (m, 3 H), 1.72-1.62 (m, 4
H), 1.15 (s, 42 H), 1.14 (s, 21 H); 13C NMR (75 MHz, C6D6)
ppm 156.8, 93.8, 82.0, 81.5, 70.9, 67.1, 62.4, 39.6, 38.6, 24.6 (2
C), 18.47 (3 C), 18.43 (3 C), 18.35 (3 C), 18.28 (9 C), 12.9 (3 C),
12.8 (3 C), 12.4 (3 C); MS m/z (M+ - OH) calcd 681.5129, obsd
Exp er im en ta l Section
Gen er a l Deta ils. Consult ref 4.
3,4-Bis-O-(ter t-bu tyld im eth ylsilyl)-L-r h a m n a l (3). 3,4-
Di-O-acetyl-L-rhamnal (5.10 g, 23.8 mmol) was dissolved in
methanol (55 mL), and a small piece of sodium wire was added.
The mixture was stirred for 3 h and coconcentrated with
benzene (50 mL) to afford a golden, crystalline material which
was taken up in DMF (45 mL). Imidazole (7.81 g, 115 mmol)
was introduced followed by TBSCl (8.78 g, 58.2 mmol). The
mixture was stirred at rt for 27 h before being diluted with
ether (200 mL) and washed with water (100 mL). The aqueous
layer was extracted with ether (2 × 200 mL), and the combined
organic solutions were washed with water (200 mL), dried,
filtered, and concentrated. The residue was flash chromato-
graphed (silica gel, elution with 5% ether in hexanes) to give
7.78 g (91%) of 3: IR (CHCl3, cm-1) 1647, 1472, 1073; 1H NMR
(300 MHz, CDCl3) δ 6.27 (dd, J ) 6.2, 0.97 Hz, 1 H), 4.65 (dd,
J ) 6.2, 3.2 Hz, 1 H), 4.08-4.06 (m, 1 H), 3.93 (qd, J ) 6.6,
6.6 Hz, 1 H), 3.56 (dd, J ) 6.4, 5.0 Hz, 1 H), 1.31 (d, J ) 6.7
Hz, 3 H), 0.91-0.90 (m, 18 H), 0.11-0.09 (m, 12 H); 13C NMR
(75 MHz, CDCl3) ppm 143.0, 102.8, 75.2, 74.7, 69.3, 26.0 (3
C), 25.9 (3 C), 18.1, 18.0, 17.2, -3.7, -3.9, -4.2, -4.3; MS m/z
681.5124; [R]25 -11.2° (c 0.69, C6H6).
D
Anal. Calcd for C38H78O5Si3: C, 65.27; H, 11.24. Found:
C, 65.48; H, 11.32.
1,5-An h yd r o-3,4-bis-O-(ter t-bu tyld im eth ylsilyl)-2,6-d i-
d eoxy-1-C-(1-h yd r oxycyclob u t yl)-L-a r a bin o-h ex-1-en i-
tol (12). A solution of 37d (1.047 g, 2.92 mmol) in dry THF (9
mL) was cooled to -78 °C, treated with tert-butyllithium (8.40
mL, 14.3 mmol, 1.7 M in pentane) via syringe, warmed to 0
°C, stirred for 45 min, recooled to -78 °C, treated with
cyclobutanone (1.25 mL, 17.1 mmol) dissolved in THF (2.4 mL),
warmed to rt for 2.5 h, quenched with water (10 mL), and
diluted with ether (20 mL). The aqueous phase was extracted
with ether (3 × 20 mL), and the combined organic layers were
dried, filtered, and concentrated. Flash chromatography of the
residue (silica gel, 25% ether in hexanes/1% triethylamine)
afforded 159 mg of unreacted 3 and 738 mg of 12 (70% based
on recovered starting material) as a clear, colorless oil: IR
1
(C6H6, cm-1) 3581, 1107; H NMR (300 MHz, C6D6) δ 5.04 (d,
(M+) calcd 358.2359, obsd 358.2357; [R]21 +42.3° (c 0.86,
D
J ) 3.4 Hz, 1 H), 4.26 (dd, J ) 4.5, 4.4 Hz, 1 H), 3.94 (quint,
J ) 6.6 Hz, 1 H), 3.65 (dd, J ) 6.4, 4.8 Hz, 1 H), 2.48-2.33
(m, 2 H), 2.14-2.04 (m, 3 H), 1.81-1.60 (m, 2H), 1.31 (d, J )
6.7 Hz, 3 H), 0.98 (s, 9 H), 0.97 (s, 9 H), 0.16 (s, 3 H), 0.15 (s,
3 H), 0.13 (s, 3 H), 0.04 (s, 3 H); 13C NMR (75 MHz, C6D6)
ppm 156.3, 96.2, 75.7, 75.1, 74.8, 70.7, 34.8, 34.6, 26.3 (3 C),
26.1 (3 C), 18.4, 18.2, 17.3, 13.5, -3.5, -3.6, -3.8, -4.2; MS
m/z (M+) calcd 428.2778, obsd 428.2771; [R]20D +42.7° (c 0.965,
C6H6).
CHCl3).
3-Deoxy-4-O-(ter t-b u t yld im et h ylsilyl)-L-r h a m n a l (4).
3-Deoxy-L-rhamnal10 (588 mg, 5.15 mmol) was analogously
protected to yield 1.114 g (94%) of 4 as a colorless oil: IR
(CHCl3, cm-1) 1655, 1257, 1237, 1124, 1048; 1H NMR (300
MHz, CDCl3) δ 6.28 (dt, J ) 6.0, 2.0 Hz, 1 H), 4.60 (td, J )
5.6, 2.4 Hz, 1 H), 3.67-3.54 (m, 2 H), 2.20 (dtd, J ) 17.0, 5.6,
1.5 Hz, 1 H), 2.01 (ddt, J ) 16.5, 9.0, 2.5 Hz, 1 H), 1.28 (d, J
) 6.0 Hz, 3 H), 0.90 (s, 9 H), 0.09 (s, 3 H), 0.08 (s, 3 H); 13C
NMR (75 MHz, CDCl3) ppm 143.2, 98.3, 75.7, 69.9, 30.9, 25.7
(3 C), 17.9, 17.9, -4.2, -4.8; MS m/z (M+) calcd 228.1546, obsd
Anal. Calcd for C22H44O4Si2: C, 61.63; H, 10.34. Found:
C, 61.75; H, 10.36.
P r ototyp ica l Acid -P r om oted Sp ir ocycliza tion of th e
Ca r bin ols. Exp er im en t 1. A solution of 11 (61 mg, 0.09
mmol) in dry CH2Cl2 (40 mL) was stirred in the presence of a
catalytic quantity of camphorsulfonic acid for 1 h. Following
the addition of saturated NaHCO3 solution (25 mL), the
aqueous phase was extracted with CH2Cl2 (3 × 50 mL), and
the combined organic layers were dried and evaporated. The
crude product was purified by flash chromatography on silica
gel (elution with 2% ethyl acetate in hexanes) to give 24 as a
colorless oil (22 mg, 49%): IR (C6H6, cm-1) 1735; 1H NMR (300
MHz, C6D6) δ 6.02 (dd, J ) 10.5, 1.6 Hz, 1 H), 5.86 (dd, J )
10.5, 1.9 Hz, 1 H), 4.28 (td, J ) 8.0, 1.7 Hz, 1 H), 4.16 (dd, J
) 10.4, 2.2 Hz, 1 H), 3.93 (dd, J ) 10.4, 6.7 Hz, 1 H), 3.80
(ddd, J ) 8.1, 6.6, 2.2 Hz, 1 H), 3.00 (ddd, J ) 6.1, 13.0, 13.0
Hz, 1 H), 2.21 (td, J ) 3.7, 12.5 Hz, 1 H), 2.12-1.85 (m, 2 H),
1.73-1.66 (m, 1 H), 1.37-0.83 (series of m, 45 H); 13C NMR
(75 MHz, C6D6) ppm 207.0, 130.3, 130.1, 80.6, 76.8, 65.2, 64.5,
38.5, 36.2, 27.9, 20.7, 18.3 (6 C), 18.2 (6 C), 13.0 (3 C), 12.4 (3
228.1533; [R]20.5 -91.5° (c 1.04, CHCl3).
D
1,5-An h yd r o-2-d eoxy-1-C-(1-h yd r oxycyclobu tyl)-3,4,6-
tr is-O-(tr iisop r op ylsilyl)-D-a r a bin o-h ex-1-en itol (10). A
solution of 2 (264 mg, 0.44 mmol) in dry THF (2 mL) was cooled
to -78 °C, treated with tert-butyllithium (1.54 mL of 1.7 M in
pentane, 2.64 mmol), and stirred for 15 min at -78 °C before
being warmed to 0 °C and stirred for an additional 60 min.
After recooling to -78 °C, a solution of cyclobutanone (0.23
mL, 3.06 mmol) in dry THF (1 mL) was introduced via syringe.
The reaction mixture was allowed to warm to rt and stirred
for 2 h before being quenched with water and diluted with
ether. The aqueous layer was extracted with ether, and the
combined organic phases were dried and concentrated. Puri-
fication of the residue by flash chromatography on silica gel
(elution with 2% ethyl acetate in hexanes/1% triethyl-
amine) gave 10 (176 mg, 81%) as a colorless oil: IR (C6H6,
cm-1) 3580; 1H NMR (300 MHz, C6D6) δ 5.25 (dd, J ) 5.2, 1.5
Hz, 1 H), 4.70-4.65 (m, 1 H), 4.37 (dd, J ) 11.2, 8.2 Hz, 1 H),
4.33-4.27 (m, 2 H), 4.07 (dd, J ) 11.2, 3.8 Hz, 1 H), 2.64-
2.56 (m, 2 H), 2.43 (s, 1 H), 2.25-2.13 (m, 2 H), 1.82-1.70 (m,
2 H), 1.14 (s, 21 H), 1.13 (s, 21 H), 1.12 (s, 21 H); 13C NMR (75
MHz, C6D6) ppm 155.6, 93.8, 81.5, 75.2, 70.8, 67.0, 62.3, 35.2,
34.2, 18.43 (3 C), 18.39 (3 C), 18.32 (9 C), 18.26 (3 C), 13.4,
12.9 (3 C), 12.8 (3 C), 12.4 (3 C); MS m/z (M+) calcd 684.5001,
C); MS m/z (M+) calcd 524.3717, obsd 524.3748; [R]25 +76.5°
D
(c 0.89, C6H6).
Anal. Calcd for C29H56O4Si2: C, 66.36; H, 10.75. Found:
C, 66.12; H, 10.60.
Exp er im en t 2. A solution of 13 (754 mg, 1.70 mmol) in
dry CH2Cl2 (400 mL) containing a few milligrams of CSA was
allowed to react for 30 h. Flash chromatographic purification
(silica gel, elution with 2% ethyl acetate in hexanes/1%
triethylamine) gave 25 as a colorless solid, mp 39-40 °C (426
obsd 684.5024; [R]25 -14.3° (c 0.90, C6H6).
D
Anal. Calcd for C37H76O5Si3: C, 64.85; H, 11.18. Found:
C, 65.20; H, 11.29.
1
mg, 81%): IR (CHCl3, cm-1) 1730; H NMR (300 MHz, C6D6)
1,5-An h yd r o-2-d eoxy-1-C-(1-h yd r oxycyclop en tyl)-3,4,6-
tr is-O-(tr iisop r op ylsilyl)-D-a r a bin o-h ex-1-en itol (11). Re-
action of 2 (229 mg, 0.38 mmol) with tert-butyllithium (1.16
mL of 1.7 M in pentane, 1.98 mmol) and then cyclopentanone
(0.20 mL, 2.31 mmol) in the predescribed manner afforded 237
mg (94%) of 11 as a colorless oil: IR (C6H6, cm-1) 3590; 1H
NMR (300 MHz, C6D6) δ 5.29 (dd, J ) 5.2, 1.5 Hz, 1 H), 4.66-
4.61 (m, 1 H), 4.39-4.27 (m, 3 H), 4.07 (dd, J ) 11.1, 3.8 Hz,
δ 5.90 (dd, J ) 10.5, 1.9 Hz, 1 H), 5.75 (dd, J ) 10.5, 1.5 Hz,
1 H), 3.76 (td, J ) 8.0, 1.7 Hz, 1 H), 3.57 (qd, J ) 7.9, 6.1 Hz,
1 H), 2.80 (dt, J ) 12.7, 5.9 Hz, 1 H), 2.13 (m, 1 H), 1.97-1.88
(m, 1 H), 1.69-1.51 (m, 2 H), 1.27 (d, J ) 6.1 Hz, 3 H), 1.25-
0.97 (m, 3 H), 0.93 (s, 9 H), -0.03 (s, 6 H); 13C NMR (75 MHz,
C6D6) ppm 206.7, 131.0, 129.6, 80.9, 70.7, 70.4, 38.4, 36.0, 27.8,
25.9 (3 C), 20.9, 19.0, 18.1, -4.2, -4.7; MS m/z (M+) calcd
310.1964, obsd 310.1942; [R]25 -105.3° (c 0.95, CHCl3).
D
Anal. Calcd for C17H30O3Si: C, 65.76; H, 9.74. Found: C,
65.92; H, 9.75.
Exp er im en t 3. Stirring of 17 (228 mg, 0.443 mmol) in dry
CH2Cl2 (50 mL) for 19 h followed by flash chromatography
(silica gel, 10% ether in hexanes/1% triethylamine) yielded 117
mg (78%) of a mixture of 26 and 27 and a more polar
(22) Paquette, L. A.; Tae, J . J . Org. Chem. 1996, 61, 7860.
(23) The authors have deposited the atomic coordinates for the X-ray
structures with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.

Practical Synthesis of Spirocyclic Bis-C,C-Glycosides
J . Org. Chem., Vol. 62, No. 6, 1997 1721
unidentified material. The two major products were insepa-
rable by column chromatography, but appeared as a 1.1:1
(3 C), 19.4, 18.4 (2 C), 18.3, -2.5, -2.7, -3.8, -4.3; MS m/z
(M+) calcd 428.2778, obsd 428.2790; [R]22 +73.3° (c 0.24,
D
mixture on the basis of NMR integration: IR (CHCl3, cm-1
)
CHCl3).
1
1717, 1463, 1389, 1108, 1069, 882; H NMR (300 MHz, C6D6,
reported as a diastereomeric mixture) δ 5.95 (dt, J ) 10.4, 1.5
Hz, 1 H), 5.90 (d, J ) 10.5 Hz, 1 H), 5.81 (dd, J ) 10.4, 1.0 Hz,
1 H), 5.72 (dd, J ) 10.5, 2.0 Hz, 1 H), 4.35 (ddd, J ) 8.9, 5.7,
1.8 Hz, 1 H), 4.04 (ddd, J ) 10.7, 5.7, 1.3 Hz, 1 H), 3.97 (ddd,
J ) 4.5, 3.5, 1.0 Hz, 1 H), 3.77 (dd, J ) 11.5, 3.9 Hz, 1 H), 3.71
(dd, J ) 11.5, 4.3 Hz, 1 H), 3.63 (dd, J ) 10.7, 8.9 Hz, 1 H),
2.65 (ddd, J ) 12.8, 11.8, 5.9 Hz, 1 H), 2.53 (ddd, J ) 13.0,
9.7, 5.6 Hz, 1 H), 2.14-1.90 (m, 3 H), 1.85-1.62 (m, 3 H), 1.59-
1.41 (m, 3 H), 1.40-1.09 (m, 5H), 1.06-0.91 (m, 42 H); 13C
NMR (75 MHz, C6D6, reported as a diastereomeric mixture)
ppm 208.13, 208.08, 132.5, 131.0, 129.2, 129.0, 80.5, 79.8, 67.7,
67.6, 64.1, 63.4, 40.6, 39.3, 38.9, 38.2, 27.8 (2 C), 20.9, 20.8,
18.2 (6 C), 18.1 (6 C), 12.5 (3 C), 12.4 (3 C); MS m/z (M+) calcd
338.2277, obsd 338.2274.
Anal. Calcd for C22H44O4Si2: C, 61.63; H, 10.34. Found:
C, 61.53; H, 10.44.
Exp er im en t 8. Exposure of 14 (249 mg, 0.833 mmol) to
CSA in dry CH2Cl2 (80 mL) for 1 h, and subsequent flash
chromatography on silica gel (elution with 20% ether in
hexanes) afforded 199 mg (80%) of 37 and 43 mg (17%) of 38.
For 37: white solid, mp 47-48 °C; IR (CHCl3, cm-1) 1747,
1256, 1105; 1H NMR (300 MHz, CDCl3) δ 3.37-3.26 (m, 2 H),
2.38-2.21 (m, 3 H), 2.08-1.89 (m, 3 H), 1.76-1.47 (m, 4 H),
1.19 (d, J ) 5.7 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 6 H); 13C NMR
(75 MHz, CDCl3) ppm 216.6, 80.7, 73.9, 72.5, 35.7, 31.7, 29.8,
28.4, 25.7 (3 C), 18.6, 17.9, 17.8, -4.1, -4.7; MS m/z (M+) calcd
298.1964, obsd 298.1945; [R]22 -66.6° (c 0.38, CHCl3).
D
Anal. Calcd for C16H30O3Si: C, 64.38; H, 10.13. Found: C,
64.40; H, 10.11.
For 38: white solid, mp 62-64 °C; IR (CHCl3, cm-1) 1710,
Exp er im en t 6. Submission of 10 (53 mg, 0.08 mmol) to
reaction for 4 h and subsequent flash chromatography (silica
gel, elution with 2% ethyl acetate in hexanes) gave 27 mg
(50%) of 33 and 20 mg (38%) of 34, both as colorless oils.
1
1362, 1091; H NMR (300 MHz, CDCl3) δ 3.70 (dq, J ) 8.8,
6.2 Hz, 1 H), 3.18 (td, J ) 8.9, 4.2 Hz, 1 H), 2.46-2.35 (m, 1
H), 2.22-1.91 (m, 4 H), 1.82-1.59 (m, 5 H), 1.13 (d, J ) 6.2
Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 6 H); 13C NMR (CDCl3) ppm
216.7, 77.3, 73.3, 73.2, 38.3, 36.5, 28.9 (2 C), 25.7 (3 C), 18.7,
17.9, 17.5, -4.1, -4.7; MS m/z (M+) calcd 298.1964, obsd
1
For 33: IR (CHCl3, cm-1) 1740; H NMR (300 MHz, C6D6)
δ 4.33 (ddd, J ) 8.0, 6.0, 4.0 Hz, 1 H), 3.94 (dd, J ) 10.5, 3.5
Hz, 1 H), 3.78 (dd, J ) 10.5, 5.5 Hz, 1 H), 3.69 (dd, J ) 7.5,
6.0 Hz, 1 H), 3.52 (ddd, J ) 7.5, 5.5, 3.5 Hz, 1 H), 2.46-2.32
(m, 1 H), 2.13 (dd, J ) 13.5, 4.0 Hz, 1 H), 2.14-1.99 (m, 3 H),
1.87-1.71 (m, 2 H), 1.57 (dd, J ) 13.5, 8.0 Hz, 1 H), 1.13-
1.10 (m, 63 H); 13C NMR (75 MHz, C6D6) ppm 215.6, 78.1, 78.0,
72.6, 71.5, 64.0, 38.1, 35.3, 34.3, 18.42 (2 C), 18.35 (3 C), 18.31
(2 C), 18.29 (6 C), 17.94 (6 C), 17.8, 13.5 (3 C), 13.4 (3 C), 12.0
(3 C); MS m/z (M+ - C3H7) calcd 641.4453, obsd 641.4452;
298.1957; [R]25 +93.4 (c 0.265, CHCl3).
D
Anal. Calcd for C16H30O3Si: C, 64.38; H, 10.13. Found: C,
64.26; H, 10.14.
Exp er im en t 9. From the isomerization of 18 (223 mg,
0.447 mmol) during 30 min, there was isolated following flash
chromatography (silica gel, elution with 10% ethyl acetate in
hexanes/1% triethylamine) 140 mg (63%) of 39 and 50 mg
(22%) of 40. A small amount of 18 (9 mg, 4%) was also
recovered.
[R]25 +17.7° (c 1.53, CHCl3).
D
Anal. Calcd for C37H76O5Si3: C, 64.85; H, 11.18. Found:
C, 63.51; H, 11.15.
For 39: clear, colorless oil; IR (CHCl3, cm-1) 1734, 1464,
1
1030, 883; H NMR (300 MHz, C6D6) δ 4.74 (ddd, J ) 11.0,
1
For 34: IR (C6H6, cm-1) 1760; H NMR (300 MHz, C6D6) δ
4.5, 2.6 Hz, 1 H), 3.95 (br d, J ) 2.0 Hz, 1 H), 3.73-3.72 (m,
2 H), 2.28 (dd, J ) 12.9, 11.1 Hz, 1 H), 2.13-1.93 (m, 2 H),
1.83-1.65 (m, 2 H), 1.60 (dd, J ) 12.9, 4.5 Hz, 1 H), 1.39-
1.25 (m, 2 H), 1.17-1.16 (m, 42 H); 13C NMR (75 MHz, C6D6)
ppm 214.6, 79.0, 71.2, 67.9, 67.7, 38.2, 36.1, 33.5, 18.5 (6 C),
18.4 (6 C), 18.3, 13.1 (3 C), 12.9 (3 C); MS m/z (M+ - C3H7)
3.99 (dd, J ) 10.5, 2.5 Hz, 1 H), 3.95 (ddd, J ) 10.5, 7.5, 5.0
Hz, 1 H), 3.84 (dd, J ) 10.5, 6.0 Hz, 1 H), 3.69 (dd, J ) 8.0,
7.5 Hz, 1 H), 3.41 (ddd, J ) 8.0, 6.0, 2.5 Hz, 1 H), 1.99 (dd, J
) 13.0, 10.5 Hz, 1 H), 2.17-1.97 (m, 1 H), 1.90-1.65 (m, 1 H),
1.66 (dd, J ) 13.0, 5.0 Hz, 1 H), 1.49-1.31 (m, 2 H), 1.28-
1.15 (m, 2 H), 1.14-1.00 (m, 63 H); 13C NMR (75 MHz, C6D6)
ppm 212.8, 79.3, 78.5, 74.2, 73.8, 64.7, 36.6, 35.1, 32.4, 18.8 (3
C), 18.7 (3 C), 18.59 (3 C), 18.56 (3 C), 18.2 (6 C), 18.1, 14.2 (3
C), 14.1 (3 C), 12.3 (3 C); MS m/z [M+ - (CO + 2CH3)] calcd
calcd 455.3013, obsd 455.2963; [R]22 -55.2° (c 0.785, CHCl3).
D
Anal. Calcd for C27H54O4Si2: C, 65.00; H, 10.91. Found:
65.28; H, 10.89.
For 40: clear, colorless oil; IR (CHCl3, cm-1) 1752, 1464,
1062, 883; 1H NMR (300 MHz, C6D6) ppm 3.89-3.81 (m, 3 H),
3.22 (dd, J ) 12.2, 0.6 Hz, 1 H), 2.73 (dd, J ) 12.2, 11.9 Hz, 1
H), 2.03-1.94 (m, 1 H), 1.85-1.71 (m, 2 H), 1.59-1.50 (m, 1
H), 1.41-1.25 (m, 3 H), 1.22-1.20 (m, 21 H), 1.12-1.10 (m,
21 H); 13C NMR (75 MHz, C6D6) ppm 211.1, 80.6, 71.2, 69.9,
67.6, 35.0, 32.9, 31.9, 18.5 (3 C), 18.4 (6 C), 18.3 (3 C), 18.1,
13.3 (3 C), 12.8 (3 C); MS m/z (M+ - C3H7) calcd 455.3013,
626.4583, obsd 626.4557; [R]25 -4.1 (c 1.39, C6H6).
D
Anal. Calcd for C37H76O5Si3: C, 64.85; H, 11.18. Found:
C, 65.03; H, 11.40.
Exp er im en t 7. Isomerization of 12 (206 mg, 0.480 mmol)
in dry CH2Cl2 (40 mL) and subsequent flash chromatography
(silica gel, elution with 10% ether in hexanes) yielded 131 mg
(64%) of 35 and 29 mg (14%) of 36.
For 35: white solid, mp 55-56 °C; IR (CHCl3, cm-1) 1737,
1257, 1108, 1088, 837; 1H NMR (300 MHz, C6D6) ppm 4.61
(ddd, J ) 10.9, 8.4, 4.9 Hz, 1 H), 3.79 (dq, J ) 8.9, 6.3 Hz, 1
H), 3.19 (t, J ) 8.7 Hz, 1 H), 2.12-2.02 (m, 1 H), 1.91 (dd, J
) 13.4, 5.0 Hz, 1 H), 1.86-1.61 (m, 3 H), 1.63 (dd, J ) 13.4,
11.0 Hz, 1 H), 1.26 (d, J ) 6.3 Hz, 3 H), 1.31-1.08 (m, 2 H),
1.03 (s, 9 H), 1.00 (s, 9 H), 0.24 (s, 3 H), 0.21 (s, 3 H), 0.18 (s,
3 H), 0.06 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 214.5, 79.3,
78.9, 72.7, 70.9, 39.1, 38.0, 35.8, 26.5 (3 C), 26.4 (3 C), 19.4,
18.4, 18.3, 18.1, -2.3, -2.8, -3.6, -4.2; MS m/z (M+) calcd
obsd 455.2938; [R]22 -2.81° (c 1.295, CHCl3).
D
Anal. Calcd for C27H54O4Si2: C, 65.00; H, 10.91. Found:
C, 64.90; H, 10.93.
Exp er im en t 10. From the isomerization of 20 (179 mg,
0.278 mmol) in CH2Cl2 (20 mL) during 30 min, there was
isolated following flash chromatography (silica gel, elution with
5% ethyl acetate in hexanes/1% triethylamine) 124 mg (70%)
of 41 and 34 mg (19%) of 42.
For 41: colorless oil; IR (CHCl3, cm-1) 1751, 1463, 1110,
1
1063; H NMR (300 MHz, C6D6) δ 4.06 (br s, 1 H), 4.00-3.86
428.2778, obsd 428.2792; [R]20 -45.5° (c 0.95, CHCl3).
D
(m, 3 H), 3.52 (t, J ) 6.3 Hz, 1 H), 2.73 (t, J ) 12.3 Hz, 1 H),
2.12-1.90 (m, 2 H), 1.82-1.62 (m, 2 H), 1.48-1.23 (m, 3H),
1.12-1.10 (m, 51 H), 0.33 (s, 3 H), 0.24 (s, 3 H); 13C NMR (75
MHz, C6D6) ppm 210.8, 80.5, 77.0, 71.3, 70.7, 63.9, 35.0, 32.4,
32.3 (2 C), 26.4 (3 C), 18.9, 18.4 (3 C), 18.3 (3 C), 18.2 (6 C),
12.8 (3 C), 12.3 (3 C), -3.25, -4.3; MS m/z (M+ - C3H7) calcd
Anal. Calcd for C22H44O4Si2: C, 61.63; H, 10.34. Found:
C, 62.01; H, 10.37.
For 36: white solid, mp 105-107 °C; IR (CHCl3, cm-1) 1749,
1472, 1257, 1215, 1109, 1066; 1H NMR (300 MHz, C6D6) δ 3.71
(ddd, J ) 11.8, 8.1, 4.6 Hz, 1 H), 3.32 (dq, J ) 8.9, 6.1 Hz, 1
H), 3.20 (t, J ) 8.5 Hz, 1 H), 2.10 (t, J ) 12.8 Hz, 1 H), 2.04-
1.90 (m, 1 H), 1.77-1.64 (m, 2 H), 1.59 (dd, J ) 12.9, 4.6 Hz,
1 H), 1.47 (ddd, J ) 12.5, 9.2, 6.5 Hz, 1 H), 1.43-1.33 (ddd, J
) 13.1, 6.8, 6.4 Hz, 1 H), 1.27 (d, J ) 6.1 Hz, 3H), 1.23-1.13
(m, 1 H), 1.01 (s, 9 H), 0.96 (s, 9 H), 0.19 (s, 3 H), 0.14 (s, 3 H),
0.05 (s, 3H), -0.00 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm
212.0, 79.9, 78.9, 72.9, 72.8, 38.6, 35.3, 32.3, 26.5 (3 C), 26.4
599.3983, obsd 599.3957; [R]22 -5.13° (c 1.11, CHCl3).
D
Anal. Calcd for C34H70O5Si3: C, 63.49; H, 10.97. Found:
C, 63.76; H, 10.88.
For 42: pale yellowish oil; IR (CHCl3, cm-1) 1735, 1463,
1
1110, 1057; H NMR (300 MHz, C6D6) δ 4.82 (ddd, J ) 11.5,
4.6, 2.2 Hz, 1 H), 4.19 (d, J ) 0.7 Hz, 1 H), 4.04-3.88 (m, 3H),
2.30 (dd, J ) 12.6, 11.8 Hz, 1 H), 2.20-2.09 (m, 1 H), 1.97-

1722 J . Org. Chem., Vol. 62, No. 6, 1997
Paquette et al.
1.67 (m, 3 H), 1.62 (ddd, J ) 12.8, 4.6, 0.7 Hz, 1 H), 1.40-1.26
(m, 2 H), 1.20-1.01 (m, 51 H), 0.36 (s, 3 H), 0.28 (s, 3 H); 13C
NMR (75 MHz, C6D6) ppm 214.6, 78.9, 76.3, 70.4, 68.6, 63.1,
38.0, 35.7, 33.0 (2 C), 26.2 (3 C), 18.7, 18.2 (3 C), 18.1 (3 C),
100.6, 87.4, 74.4, 70.7, 70.4, 63.6, 36.2, 34.4, 33.0, 26.4 (3 C),
25.1, 25.0, 18.8, 18.5 (3 C), 18.4 (3 C), 18.2 (6 C), 12.8 (3 C),
12.4 (3 C), -3.2, -4.5; MS m/z (M+ - C3H7 - H2O) calcd
613.4140, obsd 613.4161; [R]21 +16.0° (c 0.95, CHCl3).
D
17.9 (6 C), 12.6 (3 C), 12.0 (3 C), -3.5, -4.6; MS m/z (M+
-
Anal. Calcd for C35H74O6Si3: C, 62.26; H, 11.05. Found:
C, 62.10; H, 11.13.
C3H7) calcd 599.3983, obsd 599.4031; [R]24 +26.8° (c 1.06,
D
CHCl3).
Acid -Ca ta lyzed Hyd r a tion of 23. Analogous processing
of 23 (176 mg, 0.398 mmol) provided 137 mg (75%) of 46 as a
white solid, mp 74.5-76 °C: IR (CHCl3, cm-1) 3556, 1471,
1389, 1362, 1254, 1043, 837; 1H NMR (300 MHz, C6D6) δ 4.27
(ddd, J ) 11.5, 4.6, 2.3 Hz, 1 H), 3.86 (q, J ) 6.4 Hz, 1 H),
3.50-3.49 (m, 1 H), 3.09 (d, J ) 2.2 Hz, 1 H), 2.17 (ddd, J )
12.1, 11.5, 2.0 Hz, 1 H), 2.08-1.98 (m, 1 H), 1.89 (s, 1 H), 1.80
(dd, J ) 12.1, 4.6 Hz, 1 H), 1.77-1.63 (m, 4 H), 1.56-1.43 (m,
3 H), 1.11 (d, J ) 6.5 Hz, 3 H), 1.06 (s, 9 H), 0.99 (s, 9 H), 0.27
(s, 3 H), 0.15 (s, 3 H), 0.14 (s, 3 H), 0.13 (s, 3 H); 13C NMR (75
MHz, C6D6) ppm 100.2, 87.2, 73.9, 70.5, 68.8, 36.0, 34.2, 32.3,
26.4 (3 C), 26.3 (3 C), 25.0, 24.9, 18.8, 18.7, 18.2, -3.2, -4.1,
-4.4, -4.5; MS m/z (M+ - C4H9) calcd 403.2336, obsd
Anal. Calcd for C34H70O5Si3: C, 63.49; H, 10.97. Found:
C, 63.22; H, 10.94.
Exp er im en t 11. Stirring of 22 (239 mg, 0.557 mmol) in
dry CH2Cl2 (45 mL) containing a catalytic quantity of CSA for
1 h with subsequent chromatography on silica gel (elution with
10% ethyl acetate in hexanes) provided 149 mg (62%) of 43
and 73 mg (30%) of 44.
For 43: white solid, mp 88-89 °C; IR (CHCl3, cm-1) 1751,
1
1471, 1372, 1255, 1109, 1069, 1031, 835; H NMR (300 MHz,
C6D6) δ 3.68 (ddd, J ) 12.2, 4.1, 2.4 Hz, 1 H), 3.41 (t, J ) 1.0
Hz, 1 H), 3.22 (q, J ) 6.2 Hz, 1 H), 2.58 (t, J ) 12.3 Hz, 1 H),
2.05-1.95 (m, 1 H), 1.81-1.66 (m, 2 H), 1.60-1.48 (m, 1 H),
1.27 (dd, J ) 12.2, 6.8 Hz, 1 H), 1.31-1.19 (m, 1 H), 1.17 (d,
J ) 6.3 Hz, 3 H), 1.08 (s, 9 H), 1.05 (ddd, J ) 12.2, 4.2, 0.9 Hz,
1 H), 0.97 (s, 9 H), 0.26 (s, 3 H), 0.12 (s, 3 H), 0.08 (s, 3 H),
0.07 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 211.1, 80.2, 73.8,
71.4, 71.2, 35.1, 32.1, 32.0, 26.4 (6 C), 18.9 (2 C), 18.7, 18.3,
-3.4, -4.2, -4.3, -4.5; MS m/z (M+ - C4H9) calcd 371.2074,
403.2375; [R]21 -28.2° (c 0.97, CHCl3).
D
Anal. Calcd for C23H48O5Si2: C, 59.95; H, 10.50. Found:
C, 60.06; H, 10.58.
(6S,9S,9S,10S)-9,10-Bis(ter t-b u t yld im et h ylsiloxy)-8-
m eth yl-1,7-d ioxa sp ir o[5.5]u n d eca n -2-on e (49). A cold (0
°C), magnetically stirred mixture of 35 (238 mg, 0.56 mmol)
and sodium bicarbonate (252 mg, 3.00 mmol) in CH2Cl2 (10
mL) was treated with m-chloroperbenzoic acid (315 mg of 50-
60% purity, ca. 1 mmol) and stirred for 30 min at 0 °C and 10
min at 25 °C. Following the addition of 10% Na2SO3 solution
(15 mL) and a further 1 h of stirring, the phases were
separated and the aqueous layer was extracted with CH2Cl2.
The combined organic solutions were washed with saturated
NaHCO3 solution and brine, dried, and concentrated. Puri-
fication of the residue by flash chromatography on silica gel
(elution with 10% ethyl acetate in hexanes) furnished 237 mg
(98% based on recovered 35) of 49 as colorless crystals, mp 98
°C: IR (CHCl3, cm-1) 1735; 1H NMR (300 MHz, CDCl3) δ 4.08
(ddd, J ) 4.9, 8.2, 10.9 Hz, 1 H), 3.81 (dq, J ) 6.3, 9.1 Hz, 1
H), 3.17 (dd, J ) 8.4, 8.8 Hz, 1 H), 2.67-2.57 (m, 1 H), 2.48-
2.36 (m, 1 H), 2.19 (dd, J ) 4.9, 13.4 Hz, 1 H), 2.15-2.05 (m,
1 H), 1.93-1.79 (m, 1 H), 1.78-1.69 (m, 2 H), 1.62 (dd, J )
10.9, 13.4 Hz, 1 H), 1.19 (d, J ) 6.3 Hz, 3 H), 0.90 (s, 9 H),
0.89 (s, 9 H), 0.10 (s, 3 H), 0.09 (s, 6 H), 0.07 (s, 3 H); 13C NMR
(75 MHz, CDCl3) ppm 171.1, 103.7, 78.0, 71.1, 70.0, 44.3, 32.5,
29.3, 26.3 (3 C), 26.1 (3 C), 18.8, 18.2, 18.0, 15.5, -2.7, -3.2,
-3.9, -4.3; MS m/z (M+ - CO, C(CH3)3, - 2CH3) calcd
obsd 371.2067; [R]21 +7.96° (c 1.08, CHCl3).
D
Anal. Calcd for C22H44O4Si2: C, 61.63; H, 10.34. Found:
C, 61.74; H, 10.29.
For 44: IR (CHCl3, cm-1) 1734, 1471, 1255, 1107, 1062,
1
1035, 835; H NMR (300 MHz, C6D6) δ 4.69 (ddd, J ) 11.6,
4.6, 2.4 Hz, 1 H), 3.78 (q, J ) 6.4 Hz, 1 H), 3.48 (d, J ) 2.0 Hz,
1 H), 2.12 (t, J ) 12.1 Hz, 1 H), 2.11-2.03 (m, 1 H), 1.92-1.77
(m, 2 H), 1.75-1.61 (m, 1 H), 1.42 (dd, J ) 12.7, 4.6 Hz, 1 H),
1.30-1.20 (m, 2 H), 1.11 (d, J ) 6.4 Hz, 3 H), 1.06 (s, 9 H),
1.02 (s, 9 H), 0.26 (s, 3 H), 0.19 (s, 3 H), 0.17 (s, 3 H), 0.10 (s,
3 H); 13C NMR (75 MHz, C6D6) ppm 215.1, 78.9, 74.0, 71.3,
69.0, 38.4, 36.1, 32.5, 26.5 (3 C), 26.4 (3 C), 18.9 (2 C), 18.7,
18.2, -3.3, -4.0, -4.3, -4.4; MS m/z (M+) calcd 371.2074, obsd
371.2071; [R]21 -55.6° (c 1.22, CHCl3).
D
The stereochemistry of the spiro center of 44 was deter-
1
mined in a similar manner. A 1H-1H COSY 90 and a H-13C
phase sensitive correlation experiment along with measure-
ment of coupling constants enabled unambiguous assignment
of all proton and carbon signals. Because the signals for H(2a)
and H(8) were not completely resolved by 1H NMR, clean
irradiation of H(2a) could not be achieved. However, semise-
lective irradiation of the parent triplet representing H(2a) led
to strong enhancement of the carbonyl carbon (C(7). Addition-
ally, C(1), C(3), and C(10) were also enhanced, although the
signal for C(10) was not as intense. Several NOE experiments
were also performed to confirm the stereochemistry of the spiro
center. A significant NOE enhancement (2.6%) was observed
between H(2e) and H(10′) when H(2e) was irradiated. On this
basis, the spirocyclic carbon must be of the R configuration.
Acid -Ca ta lyzed Hyd r a tion of 21. A solution of 21 (82
mg, 0.125 mmol) in dry CH2Cl2 (17 mL) containing a catalytic
quantity of CSA was stirred for 3 h and worked up in the usual
way. Chromatography on silica gel (elution with 5% ethyl
acetate in hexanes/1% triethylamine) provided 62 mg (73%)
of 45 as a colorless oil: IR (CHCl3, cm-1) 3550, 1463, 1389,
329.1604, obsd 329.1613; [R]25 -38.8° (c 0.96, CHCl3).
D
Anal. Calcd for C22H44O5Si2: C, 59.41; H, 9.97. Found: C,
59.56; H, 10.05.
Ack n ow led gm en t. We thank the National Science
Foundation for financial support, Paul Lobben for
extensive 2D NMR experiments, Dr. J udith Gallucci for
the X-ray crystallographic analysis, and Dr. Kurt Loen-
ing for assistance with nomenclature.
Su p p or tin g In for m a tion Ava ila ble: A considerable por-
tion of the Experimental Section, NOE and long-range DEPT
data for 29, 35, 36, 39, 40, 41, and 43, and an ORTEP drawing
for 37 (13 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
1
1366, 1251, 1044; H NMR (300 MHz, C6D6) δ 4.44 (ddd, J )
11.4, 4.4, 2.0 Hz, 1 H), 4.13-4.08 (m, 2 H), 3.99-3.86 (m, 2
H), 3.45 (d, J ) 2.2 Hz, 1 H), 2.32 (ddd, J ) 11.8, 11.4, 2.1 Hz,
1 H), 2.12-2.06 (m, 2 H), 1.98-1.93 (dd, J ) 11.8, 4.2 Hz, 1
H), 1.83-1.71 (m, 3 H), 1.62-1.47 (m, 2 H), 1.29-1.03 (m, 53
H), 0.33 (s, 3 H), 0.26 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm
J O962020I