Studies on Mercury(II)-Mediated Opening of Bi- and Tercyclopropane Arrays

Article abstract of DOI:10.1021/jo970464o

The first examples of the mercury(II)-mediated ring opening of bicyclopropane and tercyclopropane arrays have been investigated. The presence of an adjacent cyclopropyl group dramatically increased the rate of the mercury-mediated opening of the first cyclopropane in a cyclopropane array. In contrast to the mercury-mediated ring opening of monocyclopropanes which usually undergo a concerted ring-opening mechanism, electrophilic openings of cyclopropane arrays occurred through a stabilized, free carbocation. Excellent regio- and stereoselectivities were observed in the mercury- mediated intramolecular openings of the second cyclopropanes in the cyclopropane arrays, giving rise to the formation of enantiomerically pure, highly substituted tetrahydrofurans.

Full text of DOI:10.1021/jo970464o

J . Org. Chem. 1997, 62, 4653-4664
4653
Stu d ies on Mer cu r y(II)-Med ia ted Op en in g of Bi- a n d
Ter cyclop r op a n e Ar r a ys
Anthony G. M. Barrett* and William Tam
Department of Chemistry, Imperial College of Science, Technology and Medicine, London, SW7 2AY, U.K.
Received March 13, 1997X
The first examples of the mercury(II)-mediated ring opening of bicyclopropane and tercyclopropane
arrays have been investigated. The presence of an adjacent cyclopropyl group dramatically increased
the rate of the mercury-mediated opening of the first cyclopropane in a cyclopropane array. In
contrast to the mercury-mediated ring opening of monocyclopropanes which usually undergo a
concerted ring-opening mechanism, electrophilic openings of cyclopropane arrays occurred through
a stabilized, free carbocation. Excellent regio- and stereoselectivities were observed in the mercury-
mediated intramolecular openings of the second cyclopropanes in the cyclopropane arrays, giving
rise to the formation of enantiomerically pure, highly substituted tetrahydrofurans.
In tr od u ction
FR-900848 (1), which was isolated from the fermenta-
tion broth of Streptoverticillium fervens by Yoshida and
co-workers at Fujisawa in 1990,1 shows potent, selective
activity against filamentous fungi such as Aspergillus
niger, Mucor rouxianus, Aureobasidium pullulans, and
various Trichophyton sp., etc. In contrast it is essentially
inactive against nonfilamentous fungi including Candida
albicans and Gram-positive and -negative bacteria. An-
other structurally related cholesteryl ester transfer pro-
tein inhibitor U-106305 (2) was recently isolated by
Upjohn scientists from the fermentation broth of Strep-
tomyces sp. UC 11136.2 U-106305 (2) is a potent in vitro
inhibitor of the cholesteryl ester transfer protein (CETP)
reaction, thus being of potential application in the
F igu r e 1.
prevention of arteriosclerosis.3 These compounds are
structurally remarkable as they contain a quartercyclo-
propane array and a quinquecyclopropane array, respec-
tively (Figure 1). We have recently reported the total
syntheses of FR-900848 and U-106305.4-6 During the
studies of the total syntheses and the structural assign-
ments of these cyclopropane array-containing natural
products, we have developed an efficient, bidirectional
approach to the enantioselective synthesis of cyclopro-
pane arrays such as 3-8 (Figure 2).7
Although the electrophilic carbon-carbon bond cleav-
age in cyclopropanes has been subjected to considerable
investigation and speculation, no systematic study on the
F igu r e 2.
X Abstract published in Advance ACS Abstracts, J une 15, 1997.
(1) Yoshida, M.; Ezaki, M.; Hashimoto, M.; Yamashita, M.; Shige-
matsu, N.; Okuhara, M.; Hotikoshi, K. J . Antibiot. 1990, 18, 748.
(2) Kuo, M. S.; Zielinski, R. J .; Cialdella, J . I.; Marschke, C. K.;
Dupuis, M. J .; Li, G. P.; Kloosterman, D. A.; Spilman, C. H.; Marshall,
V. P. J . Am. Chem. Soc. 1995, 117, 10629.
cleavage of multiple cyclopropane arrays has been
reported.8-10 In this paper we report our studies on the
(3) For recent review, see: Yalpani, M. Chem. Ind. 1996, 85.
(4) (a) Barrett, A. G. M.; Kasdorf, K. Chem. Commun. 1996, 325.
(b) Barrett, A. G. M.; Kasdorf, K. J . Am. Chem. Soc. 1996, 118, 11030.
(5) Barrett, A. G. M.; Hamprecht, D.; White, A. J . P.; Williams, D.
J . J . Am. Chem. Soc. 1996, 118, 7863.
(6) For a second total synthesis of FR-900848, see: (a) Falck, J . R.;
Mekonnen, B.; Yu, J .; Lai, J . Y. J . Am. Chem. Soc. 1996, 118, 6096.
For a second total synthesis of U-106305, see: (b) Charette, A. B.;
Helene, L. J . Am. Chem. Soc. 1996, 118, 10327.
(7) (a) Barrett, A. G. M.; Kasdorf, K.; Williams, D. J . J . Chem. Soc.,
Chem. Commun. 1994, 1781. (b) Barrett, A. G. M.; Tustin, G. J . J .
Chem. Soc., Chem. Commun. 1995, 355. (c) Barrett, A. G. M.;
Doubleday, W. W.; Kasdorf, K.; Tustin, G.; White, A. J . P.; Williams,
D. J . J . Chem. Soc., Chem. Commun. 1995, 407. (d) Barrett, A. G. M.;
Kasdorf, K.; White, A. J . P.; Williams, D. J . J . Chem. Soc., Chem.
Commun. 1995, 649. (e) Barrett, A. G. M.; Doubleday, W. W.; Tustin,
G. Tetrahedron 1996, 52, 15325.
(8) For reviews on cleavage of cyclopropanes, see: (a) Preston, P.
M.; Tennant, G. Chem. Rev. 1972, 72, 627. (b) DePuy, C. H. Top. Curr.
Chem. 1973, 40, 73. (c) Gibson, D. H.; DePuy, C. H. Chem. Rev. 1974,
74, 605. (d) Crabtree, R. H. Chem. Rev. 1985, 85, 245. (e) Rappoport,
Z., Ed. The Chemistry of the Cyclopropyl Group, Parts 1 and 2; J . Wiley
and Sons: London, 1987.
(9) For examples in mercury-induced ring opening of cyclopropanes,
see: (a) Lukina, R.; Gladshetein, M. Dokl. Akad. Nauk SSSR 1950,
71, 65. (b) DePuy, C. H.; MsGuirk, R. H. J . Am. Chem. Soc. 1973, 95,
2366. (c) Collum, D. B.; Mohamadi, F.; Hallock, J . S. J . Am. Chem.
Soc. 1983, 105, 6882. (d) Collum, D. B.; Still, W. C.; Mohamadi, F. J .
Am. Chem. Soc. 1986, 108, 2094. (e) Lambert, J . B.; Chelius, E. C.;
Bible, R. H., J r.; Hajdu, E. J . Am. Chem. Soc. 1991, 113, 1331. (f)
Kocovsky, P.; Srogl, J .; Pour, M.; Gogoll, A. J . Am. Chem. Soc. 1994,
116, 186. (g) Kocovsky, P.; Grech, J . M.; Mitchell, W. J . Org. Chem.
1995, 60, 1482.
S0022-3263(97)00464-7 CCC: $14.00 © 1997 American Chemical Society

4654 J . Org. Chem., Vol. 62, No. 14, 1997
Barrett and Tam
on an adjacent carbon atom.11a A recent report by Kirmse
and co-workers showed that a cyclopropyl group can
stabilize an adjacent carbocation and the rate of trapping
of the cyclopropylcarbinyl cation by an external nucleo-
phile is much faster than the rate of rearrangement to
form cyclobutenes (eq 2).11b In an electrophilic ring
opening of a cyclopropane array such as bicyclopropane
3 (Scheme 1), formation of free carbocation 16 (that can
be stabilized by the adjacent cyclopropyl group) may be
a more favorable pathway than the usual concerted ring
opening which proceeds through the intermediate 15.
F igu r e 3.
Sch em e 1. P ossible Rea ction P a th w a ys of th e
Mer cu r y-Med ia ted Op en in g of
Bicyclop r op a n ed im eth a n ol 3
Resu lts a n d Discu ssion
Bicyclopropanedimethanol 3 was prepared from mu-
condiol 17 via the Charette cyclopropanation12 in the
presence of the chiral auxiliary 18 (eq 3).7b When the
mercury-mediated opening of the bicyclopropane arrays
(3 and 4) and tercyclopropane array (5).
Mercury-mediated opening of monocyclopropanes are
well-documented and are known to occur with high regio-
and stereoselectivity.9 For example, when cyclopropane
9 was allowed to react with mercuric trifluoroacetate
(Hg(OCOCF3)2) followed by addition of sodium chloride
and a reductive workup (LiAlH4, THF), the cyclopropane
was cleaved regioselectively (at C3-C4 only) and stereo-
selectively (inversion-retention at C4 ) 45:1), eq 1.9d The
regioselectivity of the electrophilic opening of cyclopro-
pane can be explained by the fact that bond C3-C4 is the
most electron-rich bond in the cyclopropane as both bonds
C2-C3 and C2-C4 are relatively electron poor due to the
inductive effect of the neighboring electron-withdrawing
group (CH2OH). The high level of stereoselectivity can
be explained by a concerted mechanism in which bond
breaking (C3-C4) and bond forming (C-HgOR and
C-OCOCF3) occur at almost the same time (Figure 3).
bicyclopropanedimethanol 3 was allowed to react with 2
equiv of mercuric trifluoroacetate (Hg(OCOCF3)2) in
methanol at room temperature, the starting material was
consumed within 20 min. Addition of solid NaCl followed
by reductive demercuration with LiAlH4 in THF at 0 °C
afforded a 1:1 inseparable mixture of stereoisomers (eq
4). When benzyl alcohol (BnOH) was used instead of
MeOH as the solvent (and as the nucleophile), mercury-
mediated opening of the bicyclopropanedimethanol 3
resulted in a 1:1.2 separable mixture of organomercurial
chlorides (Scheme 2). Once again this ring-opening
reaction was complete within 20 min. Reductive demer-
curation of the organomercurial chlorides 21 and 22
provided the monocyclopropanes 23 and 24 in good yields.
It is well-known that a cyclopropyl group is uncom-
monly efficient at stablizing a positive charge generated
(10) For representative examples of opening of cyclopropanes by
metals other than mercury, see the follow. Thallium: (a) Kocovsky,
P.; Pour, M.; Gogoll, A. Hanus, V.; Smrcina, M. J . Am. Chem. Soc.
1990, 112, 6735. (b) Kocovsky, P.; Srogl, J .; Pour, M.; Gogoll, A. J .
Am. Chem. Soc. 1994, 116, 186. Palladium: (c) Ba¨ckvall, J . E.;
Bjo¨rkman, E. E.; Pettersson, L.; Siegbahn, P.; Strich, A. J . Am. Chem.
Soc. 1985, 107, 7408. (d) Blomberg, M. R. A.; Siegbahn, P. E. M.;
Ba¨ckvall, J . E. J . Am. Chem. Soc. 1987, 109, 4405. Platinum: (e) Ikura,
K.; Kambe, N.; Sonoda, N. J . Am. Chem. Soc. 1992, 114, 1520. (f)
Stewart, F. F.; Neilsen, W. D.; Ekeland, R. E.; Larsen, R. D.; J ennings,
P. W. Organometallics 1993, 12, 4858. Rhodium: (g) Gassman, P. G.;
Bonser, S. M. Tetrahedron Lett. 1983, 24, 3431. Iridium: (h) Campbell,
W. H.; J ennings, P. W. Organometallics 1983, 2, 1460.
Very little change in the stereoselectivity was observed
on using various mercury salts (Hg(OCOCF3)2, Hg(OAc)2,
Hg(NO3)2, and Hg(OClO3)2) or using a cosolvent (DME,
(11) (a) Hart, H.; Law, P. A. J . Am. Chem. Soc. 1964, 86, 1957. (b)
Kirmse, W.; Krzossa, B.; Steenken, S. J . Am. Chem. Soc. 1996, 118,
7473. (c) For a review on rearrangements and eliminations of cyclo-
propylcarbinyl cations, see: Olah, G. A.; Reddy, V. P.; Prakash, G. K.
S. Chem. Rev. 1992, 92, 69.
(12) Charette, A. B.; J uteau, H. J . Am. Chem. Soc. 1994, 116, 2651.

Hg(II)-Mediated Opening of Bi- and Tercyclopropane Arrays
J . Org. Chem., Vol. 62, No. 14, 1997 4655
Sch em e 2. Mer cu r y-Med ia ted Op en in g of
Bicyclop r op a n ed im eth a n ol 3
Sch em e 3. F or m a tion of Aceton id es 26 a n d 28
Sch em e 4. Mer cu r y-Med ia ted In tr a m olecu la r
Op en in gs of 23 a n d 24
CH2Cl2, THF, toluene, and CCl4). The stereoselectivity
varied from 1:1 to 1:1.5 in slight favor of isomer 22. The
yields of the ring-opening reactions remained high (65-
85%) with the use of different mercury salts but de-
creased dramatically to 40-50% when a nonpolar cosol-
vent was used. In all these cases, the ring-opening
reaction was complete within 20 min. Lowering the
temperature of the mercury-induced ring-opening reac-
tion led to a slight increase in stereoselectivity, eventually
giving a 1.5:1 ratio in favor of isomer 21 at -30 °C albeit
at a slower rate of reaction. At 0 °C, the ring-opening
reaction was complete in 20 min, -20 °C required 2.5 h
and -30 °C required 12 h. Very little reaction was
observed when the reaction temperature was reduced
further.
The rate of these mercury-mediated openings of the
bicyclopropanedimethanol 3 was much faster than the
ring opening of normal monocyclopropanes under similar
reaction conditions. Mercury-mediated opening of mono-
cyclopropanes usually requires 18 h to 5 days for the
reactions to go to completion.9 The rapid ring opening
of the first cyclopropane in a bicyclopropane array as well
as the unusual random formation of the two stereoiso-
mers can be explained by the formation of the stabilized
cyclopropylcarbinyl cation as suggested previously in
Scheme 1. Thus, the rate of the first cyclopropane ring
opening was enhanced by an adjacent cyclopropyl group,
and instead of undergoing the usual concerted electro-
philic ring-opening pathway (as in a normal monocyclo-
propane, Figure 3), a stabilized, free carbocation was
formed which explained the lack of stereoselectivity in
the formation of the ether residue.
shown in Table 1, these anti and syn acetonides 26 and
28 showed a great difference in the coupling constants
and these values matched perfectly with those reported
in the literature.13
When the monocyclopropanes 23 and 24 were allowed
to react with 2 equiv of Hg(OCOCF3)2 in CH2Cl2 at room
temperature, intramolecular ring openings occurred to
provide tetrahydrofurans 29 and 31 (Scheme 4). Reduc-
tive demercuration of 29 and 31 with LiAlH4 afforded
the highly substituted tetrahydrofurans 30 and 32. The
ring opening of the second cyclopropanes (i.e., the re-
maining cyclopropanes in 23 and 24) required a much
longer time (48 h) to go to completion as compared with
the rate of opening of the first cyclopropanes, even though
the second ring-opening reactions were intramolecular
processes. As expected from literature precedent,9c these
intramolecular ring-opening reactions were highly regio-
and stereoselective, generating single regio- and stere-
oisomers 29 and 31 with inversion of configuration at the
carbon attacked by the internal nucleophile. Formation
of the other regioisomers such as 33/34 with a six-
membered ring instead of a five-membered ring and the
other stereoisomers such as 35/36 with retention of
configuration at the carbon attacked by the internal
nucleophile were not observed in these cases (Figure 4).
The structure and stereochemistry of the tetrahydro-
furans 30 and 32 were assigned by high-field NMR
studies (HETCOR, HCOSY, and NOE experiments),
Table 2. These data from NOE studies agreed with the
previous stereochemistry assignments of the OBn groups
in the first cyclopropane ring openings (23 and 24) as
determined by the coupling constants of the acetonides
26 and 28 (Scheme 3 and Table 1).
The regiochemistry of the mercury-mediated ring
opening was confirmed by high-field NMR studies (HET-
COR and HCOSY experiments). The stereochemistries
of 23 and 24 were assigned by converting to the corre-
sponding acetonides 26 and 28 and comparison of the
coupling constants.13 Thus, hydrogenolysis of 23 and 24
afforded triols 25 and 27. Formation of the acetonides
26 and 28 was achieved by treating triols 25 and 27 using
1 equiv of 2,2-dimethoxypropane with a catalytic amount
of pyridinium p-toluenesulfonate in DMF (Scheme 3). As
(13) The assignments of these types of anti and syn 1,3-diols by
comparing the coupling constants of the corresponding acetonides have
been used widely in the literature. For an excellent example, see:
Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am. Chem. Soc. 1988,
110, 3560.

4656 J . Org. Chem., Vol. 62, No. 14, 1997
Ta ble 1. Cou p lin g Con sta n ts fr om Aceton id es Der ived fr om Tr iols 25 a n d 27
Barrett and Tam
Ta ble 2. NOE Stu d ies of Tetr a h yd r ofu r a n s 30 a n d 32
of rearrangement of this cyclopropylcarbinyl cation is
much slower than trapping with an external nucleophile
(MeOH or BnOH) and therefore no rearrangement prod-
ucts were detected; (iii) once the first cyclopropane has
been opened up, the remaining cyclopropane became
“deactivated” by the two adjacent electron-withdrawing
CH2OR groups and did not undergo rapid intermolecular
ring opening. This is supported by that fact that the
monocyclopropane-containing acetonide 28 as well as the
monocyclopropanedimethanol 375 did not undergo ring
opening (eqs 5 and 6).
In order to further confirm the above conclusions,
bicyclopropane 39 and cyclopropane 43 were synthesized
and their mercury-mediated ring openings were studied
and compared. Dicyclopropanation of the trans-penta-
2,4-dien-1-ol (38)14 with diethylzinc and diiodomethane
provided the desired racemic bicyclopropane 39 (87%) (eq
7). Cyclopropane 43 was prepared in three steps from
2-methylpropanal via Wadsworth-Emmons olefination,15
DIBAL-H reduction of the resulting R,â-unsaturated
ester, and cyclopropanation (Scheme 5).
F igu r e 4.
When the monocyclopropane 24 was treated with
Hg(OCOCF3)2 in MeOH instead of CH2Cl2, only the
intramolecular ring-opened product (31) was isolated and
no intermolecular ring-opened product(s) with MeOH was
observed. When the monocyclopropane-containing ac-
etonide 28 was submitted to the usual mercury-mediated
ring-opening conditions, no reaction was observed even
after 7 days (eq 5). On the basis of these results and the
As expected, when the bicyclopropane 39 was allowed
to react with Hg(OCOCF3)2 in MeOH, the starting
material was consumed within 15 min. Under the same
conditions, monocyclopropane 43 required 10 days for the
reaction to go to completion. Thus, the cyclopropyl group
did show a significant enhancement on the rate of ring
opening. As expected from literature precedent,9d high
stereoselectivity (with inversion at the carbon attacked
by the nucleophile, MeOH) was observed in the ring
opening of 43. Indeed, only one single diastereomer was
studies on the first and the second ring openings (vide
infra), several features of the mercury-mediated ring
opening of the cyclopropane array bicyclopropanedimeth-
anol 3 can be concluded: (i) the presence of the cyclo-
propyl group enhances the rate of the mercury-mediated
ring opening of the first cyclopropane; (ii) the first
cyclopropane ring opening in a bicyclopropanedimethanol
is probably via a free carbocation and this cation is
stabilized by the adjacent cyclopropyl group but the rate
(14) Alker, D.; Ollis, W. D.; Shahriari-Zavareh, H. J . Chem. Soc.,
Perkin Trans. 1 1990, 1637.
(15) (a) Wadsworth, W. S. Org. React. 1977, 25, 73. (b) Maryanoff,
B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.

Hg(II)-Mediated Opening of Bi- and Tercyclopropane Arrays
J . Org. Chem., Vol. 62, No. 14, 1997 4657
Sch em e 5. Syn th esis of Cyclop r op a n e 43
Sch em e 7. Syn th esis of
Bicyclop r op a n ed im eth a n ol 4
Sch em e 6. Mer cu r y-Med ia ted Op en in g of
Bicyclop r op a n e 39
Sch em e 8. Mer cu r y-Med ia ted Op en in g of
Bicyclop r op a n ed im eth a n ol 4
was allowed to react with Hg(OCOCF3)2 (2 equiv), the
starting material was once again consumed within 20
min and addition of sodium chloride afforded a 1:2.2
inseparable mixture of 51 (which also contained trace
amount of rearrangement products). Reductive demer-
curation of 51 with LiAlH4 afforded 52 and 53 in good
yields.
After study of the mercury-mediated ring opening in
the bicyclopropane array systems, we continued our
studies on the tercyclopropane array system. Thus, the
enantiomerically pure tercyclopropanedimethanol 5 was
prepared from the readily available trans-butene-1,4-diol
in four steps as previously described in our total synthesis
of U-106305.5 Based on the results on the bicyclopropane
arrays systems, vide infra, one would expect that a double
ring opening of the tercyclopropanedimethanol 5 should
occur and these ring-opening reactions should be very
fast as these cyclopropanes are “activated” by an adjacent
cyclopropane (Scheme 9). Thus, opening of the first
cyclopropane in the tercyclopropane array would lead to
the formation of the cyclopropylcarbinyl cation 54 which
is stabilized by an adjacent cyclopropyl group. Trapping
of this cation with ROH would provide the bicyclopropane
55. This bicyclopropane should undergo rapid opening
again to provide cyclopropylcarbinyl cations 56 and 57,
both of which are stabilized by a neighboring cyclopro-
pane. Trapping of these cations with ROH would lead
to the formation of the monocyclopropanes 58 and 59.
One would also expect that the reaction should stop at
this stage as the remaining cyclopropanes in these
monocyclopropanes 58 and 59 would be “deactivated” by
the two neighboring electron-withdrawing groups (CHOR)
isolated from this reaction (eq 8). In case of the mercury-
mediated ring opening of the bicyclopropane 39, a
mixture of regioisomers as well as stereoisomers was
obtained (Scheme 6). Thus, a carbocation intermediate
must have been formed in order to give such a low
stereoselectivity as compared to the high stereoselectivity
of the ring opening of 43.
It would be interesting to see if there is any difference
between the syn-bicyclopropanedimethanol (3) and the
anti-bicyclopropanedimethanol (4) in the rate and in the
stereoselectivity of the mercury-mediated ring-opening
reaction. Thus, the racemic anti-bicyclopropanedimetha-
nol (4) was synthesized based on the methodology previ-
ously developed in our group7b (Scheme 7) and the
mercury-mediated ring-opening reaction was studied
(Scheme 8). When the anti-bicyclopropanedimethanol (4)

4658 J . Org. Chem., Vol. 62, No. 14, 1997
Barrett and Tam
Sch em e 10. Ozon olysis of 60 a n d 61
Sch em e 9. P ossible P r od u cts in th e
Mer cu r y-Med ia ted Op en in g of
Ter cyclop r op a n ed im eth a n ol 5
Sch em e 11. Mer cu r y-Med ia ted In tr a m olecu la r
Op en in g of 62 a n d 64
pane 64 was also obtained from ozonolysis of 61. Sur-
prisingly, unlike the cases with cyclopropanes 23 and 24
(Scheme 4) which showed excellent regioselectivity giving
only the tetrahydrofuran ring-opened products, the mer-
cury-mediated intramolecular ring opening of cyclopro-
pane 62 afforded a 1.3:1 mixture of two regioisomers, the
tetrahydropyran 65 and the tetrahydrofuran 66 (Scheme
11). When cyclopropane 64 was allowed to react with
Hg(OCOCF3)2 under similar conditions, only one regio-
isomer, the tetrahydrofuran 67, was formed. At this
stage, we do not have a good explanation to account for
the fact that mercury-mediated intramolecular ring
opening of cyclopropanes 23, 24 (Scheme 4), and 64
(Scheme 11) gave only one regioisomer while under the
same reaction conditions cyclopropane 62 afforded two
regioisomers (Scheme 4). But it is clear that, in all cases,
only the products with inversion of configuration at the
carbon attacked by the internal nucleophile were formed.
The structures and the stereochemistry of tetrahydro-
pyran 65 and tetrahydrofurans 66 and 67 were assigned
on the basis of high-field NMR studies (HETCOR,
HCOSY, and NOE experiments).
as we observed previously in the cases of cyclopropanes
28 and 37 (eqs 5 and 6). Surprisingly, adducts 58 and
59 were not the products that we obtained in the
mercury-mediated ring opening of tercyclopropane 5.
When the tercyclopropanedimethanol 5 was allowed to
react with 3 equiv of Hg(OCOCF3)2 in MeOH at room
temperature, the starting material was consumed within
20 min. Addition of sodium chloride followed by reduc-
tive demercuration with LiAlH4 afforded a separable
mixture of stereoisomers 60 and 61 as the only isolated
products in good yield (eq 9). The structures of 60 and
61 were determined by high-field NMR studies (HETCOR
and HCOSY experiments), and the stereochemistry of the
OMe groups was determined by NOE studies of the
corresponding tetrahydrofuran derivatives (66 and 67)
as described below.
A proposed mechanism for the formation of 60 and 61
in the mercury-mediated ring-opening reaction of tercy-
clopropane 5 is shown in Scheme 12. Similar to the cases
with the bicyclopropane arrays, the first cyclopropane in
the tercyclopropane array 5 is cleaved regioselectively to
give 54 as the resulting free carbocation is stabilized by
the adjacent cyclopropyl group. This cation then under-
goes rapid rearrangement to give another cyclopropyl-
stabilized cation 68. Trapping of cation 68 with MeOH
followed by addition of NaCl and a reductive demercu-
ration will lead to the formation of the observed products
60 and 61. The rate of the rearrangement of the
cyclopropylcarbinyl cation 54 (54 f 68, Scheme 12) must
be much faster than the rate of trapping of 54 with an
external nucleophile (54 f 55, Scheme 9) in order to
provide the observed products 60 and 61. This type of
Ozonolysis of 60 followed by a reductive workup with
NaBH4 afforded the cyclopropane 62 and 2-methylpro-
pane-1,3-diol (63) (Scheme 10). Similarly, the cyclopro-

Hg(II)-Mediated Opening of Bi- and Tercyclopropane Arrays
J . Org. Chem., Vol. 62, No. 14, 1997 4659
Sch em e 12. P r op osed Mech a n ism of th e
Mer cu r y-Med ia ted Rin g Op en in g of
Ter cyclop r op a n ed im eth a n ol 5
pure, highly substituted tetrahydrofurans. Studies on
the ring-opening reactions of the higher order cyclopro-
pane arrays such as the quartercyclopropane arrays 6
and 7, and the quinquecyclopropane array such as 8
(Figure 2), as well as further investigation on the
intramolecular ring openings of these cyclopropane ar-
rays are now in progress within our laboratories.
Exp er im en ta l Section
Gen er a l. All reactions were carried out in an atmosphere
of dry nitrogen at ambient temperature unless otherwise
stated. Standard column chromatography was carried out on
BDH silica gel 60, 230-400 mesh ASTM, using flash chroma-
tography techniques (eluants are given in parentheses).16
Analytical thin-layer chromatography (TLC) was performed
on Merck precoated silica gel 60 F254 plates. All glassware
was flame dried under an inert atmosphere of dry nitrogen.
Hexanes refers to bp 40-60 °C redistilled petroleum. Solvents
were purified by distillation under N2 from CaH2 (CH2Cl2,
DMF, Et3N, pyridine); Ph2CO-Na, diethyl ether (Et2O); Ph2CO-
K, tetrahydrofuran (THF); Mg and I2, methanol (MeOH).
Bicyclopropanedimethanol 3,4a tercyclopropanedimethanol 5,5
monocyclopropanedimethanol 37,5 anti-bicyclopropane 50,7b,e
mucondiol 17,7b and trans-penta-2,4-dienyl-1-ol 3814 were
prepared as described in the literature. All other reagents
were obtained from commercial sources and used without
further purification.
Mer cu r y-Med ia ted Rin g Op en in g of (1S,3R,4R,6S)-1,6-
Bis(h yd r oxym et h yl)b icyclop r op a n e (3) w it h MeOH a s
Nu cleop h ile. Hg(O2CCF3)2 (360 mg, 0.844 mmol, 2 equiv)
was added to bicyclopropane 3 (57.8 mg, 0.406 mmol) in
anhydrous MeOH (4.5 mL). The mixture was stirred at room
temperature for 20 min when TLC indicated that all starting
material was consumed. After the solution was stirred for an
additional 40 min, solid NaCl (3 g) was added and the mixture
was stirred vigorously for 3 h. Excess NaCl was removed by
filtration, and the solids were washed with MeOH. Rotary
evaporation gave an oil which was dissolved in THF (25 mL),
and LiAlH4 (840 mg, 22.1 mmol) was added at 0 °C under N2.
After being stirred at 0 °C for 5 h, the mixture was diluted
with Et2O, a minimal amount of water and potassium sodium
tartrate were added at 0 °C, and the solution was stirred for
1 h. The mixture was filtered through silica and washed with
MeOH/Et2O (1:1), rotary evaporated, and chromatographed
(EtOAc:hexanes 0:1, 1:9, 1:3, 1:1, 3:1, 1:0) to provide an
inseparable 1:1 mixture of the products 19 and 20 as a colorless
viscous oil (65.1 mg, 0.374 mmol, 92%). These diastereomeric
diols were separated by conversion to the corresponding diester
derivative (4-biphenylcarbonyl chloride (2.5 equiv), DMAP (0.1
equiv), Et3N (5 equiv), CH2Cl2, 25 °C, 2 h), separation of these
diesters by flash column chromatography (diester of 19, Rf 0.57
(Et2O:hexanes ) 1:1); diester of 20 Rf 0.49 (Et2O:hexanes )
1:1)), followed by DIBAL-H reduction (DIBAL-H (5 equiv),
CH2Cl2, -78 °C, 2 h) of the separated diesters to provide pure
samples of 19 and 20 both as colorless oils for characterization.
(1S,3S)-3-(H yd r oxym et h yl)-1-[(1S, 2R)-3-h yd r oxy-1-
m eth oxy-2-m eth ylp r op -1-yl]cyclop r op a n e (19): Rf 0.22
Sch em e 13. Rea r r a n gem en t of
Cyclop r op ylca r bin yl Ca tion 70
rearrangement (54 f 68) was not observed in the
bicyclopropane array systems. This is probably because
this type of rearrangement would lead to the formation
of a destabilized cation (71) as this cation would be next
to an adjacent electron-withdrawing group (CH2OH),
Scheme 13. Thus, trapping of the cyclopropylcarbinyl
cation 70 with ROH to provide the monocyclopropane 72
would be the preferable process.
(EtOAc); [R]25 ) +30.8 (c ) 1.29, MeOH); IR (CHCl3) 3065
D
Con clu sion
1
(m), 3431 (br s), 1054 (s) cm-1; H NMR (CDCl3, 400 MHz) δ
3.70 (dd, 1H, J ) 10.8, 4.0 Hz), 3.57 (dd, 1H, J ) 10.8, 6.4
Hz), 3.54 (dd, 1H, J ) 11.4, 6.6 Hz), 3.46 (dd, 1H, J ) 11.4,
7.1 Hz), 3.43 (s, 3H), 2.90 (br s, 1H), 2.60 (dd, 1H, J ) 8.8, 5.8
Hz), 2.40 (br s, 1H), 1.92 (m, 1H), 1.18 (m, 1H), 0.99 (d, 3H, J
) 7.1 Hz), 0.77 (m, 1H), 0.46 (dt, 1H, J ) 8.6, 5.1 Hz), 0.39
(dt, 1H, J ) 8.6, 5.2 Hz); 13C NMR (CDCl3, 75.5 MHz) δ 89.1,
66.6, 66.6, 58.0, 40.6, 20.4, 19.2, 14.5, 7.1; MS (CI, NH3) m/ z
192 [M + NH4]+, 175 [M + H]+, 160, 143, 130, 125, 115, calcd
for C9H22NO3 ([M + NH4]+) 192.1600, found 192.1595. Anal.
Calcd for C9H18O3: C, 62.04; H, 10.41. Found: C, 62.24; H,
10.19.
We have demonstrated the first examples of mercu-
ry(II)-mediated ring opening of bi- and tercyclopropane
arrays. The presence of an adjacent cyclopropyl group
dramatically increased the rate of the mercury-mediated
opening of the first cyclopropane in a cyclopropane array.
In contrast to the mercury-mediated ring opening of
monocyclopropanes which usually undergoes a concerted
ring-opening mechanism, electrophilic openings of cyclo-
propane arrays occurred through a stabilized, free car-
bocation. Excellent regio- and stereoselectivities were
observed in the mercury-mediated intramolecular open-
ings of the second cyclopropanes in the cyclopropane
arrays, giving rise to the formation of enantiomerically
(1S ,3S )-3-(H yd r oxym e t h yl)-1-[(1R ,2R )-3-h yd r oxy-1-
m eth oxy-2-m eth ylp r op -1-yl]cyclop r op a n e (20): Rf 0.22
(16) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

4660 J . Org. Chem., Vol. 62, No. 14, 1997
Barrett and Tam
(EtOAc); [R]25D ) +4.1 (c ) 4.06, MeOH); IR (CHCl3) 3065 (m),
3401 (br s), 1079 (s), 1014 (s) cm-1; 1H NMR (CDCl3, 400 MHz)
δ 3.67 (d, 2H, J ) 5.4 Hz), 3.62 (dd, 1H, J ) 11.1, 6.3 Hz),
3.40 (s, 3H), 3.36 (dd, 1H, J ) 11.1, 7.4 Hz), 2.65 (dd, 1H, J )
8.8, 4.1 Hz), 2.53 (br s, 2H), 1.99 (m, 1H), 1.00 (d, 3H, J ) 7.2
Hz), 0.92 (m, 1H), 0.83 (m, 1H), 0.66 (dt, 1H, J ) 8.3, 5.0 Hz),
0.61 (dt, 1H, J ) 8.3, 5.0 Hz); 13C NMR (CDCl3, 75.5 MHz) δ
87.1, 65.9, 65.4, 56.6, 39.1, 17.5, 16.6, 12.2, 9.3; MS (CI, NH3)
m/ z 192 [M + NH4]+, 175 [M + H]+, 160, 143, 130, 125, 115,
calcd for C9H22NO3 ([M + NH4]+) 192.1600, found 192.1590.
Anal. Calcd for C9H18O3: C, 62.04; H, 10.41. Found: C, 62.16;
H, 10.19.
Mer cu r y-Med ia ted Rin g Op en in g of (1S,3R,4R,6S)-1,6-
Bis(h yd r oxym et h yl)b icyclop r op a n e (3) w it h Bn OH a s
Nu cleop h ile. Hg(O2CCF3)2 (12.0 g, 28.1 mmol, 2 equiv) was
added to bicyclopropane 3 (2.00 g, 14.1 mmol) in benzyl alcohol
(140 mL). The mixture was stirred at room temperature for
30 min when TLC indicated that all starting material was
consumed. After the solution was stirred for an addition 30
min, solid NaCl (100 g) was added and the reaction mixture
was stirred vigorously for 3 h. Excess NaCl was removed by
filtration, and the solids were washed with diethyl ether.
Rotary evaporation and chromatography (EtOAc:hexanes 0:1,
1:9, 1:3, 2:3, 4:1, 1:0) gave products 21 (2.48 g, 36%) and 22
(2.98 g, 44%) both as colorless viscous oils.
[M + NH4]+, 251 [M + H]+, 233 [M - H2O + H]+, 191, 160,
143, 130, 125, 108, calcd for C15H23O3 ([M + H]+) 251.1647,
found 251.1664. Anal. Calcd for C15H22O3: C, 71.97; H, 8.86.
Found: C, 71.99; H, 8.78.
(1S ,3S )-3-(H yd r oxym e t h yl)-1-[(1R ,2R )-3-h yd r oxy-2-
m eth yl-1-(p h en ylm eth oxy)p r op -1-yl]cyclop r op a n e (24).
Organomercurial diol 22 (2.98 g, 6.14 mmol) in THF (180 mL)
was added to LiAlH4 (2.55 g, 67.1 mmol) in THF (200 mL) at
0 °C under N2, and the mixture was stirred at 0 °C for 3 h.
The mixture was diluted with Et2O, a minimal amount of
water and potassium sodium tartrate were added at 0 °C, and
the mixture was stirred for 30 min. The mixture was filtered
through silica and washed with MeOH/Et2O (1:4). Rotary
evaporation and chromatography (EtOAc:hexanes 0:1, 1:9, 1:3,
1:1, 3:1, 1:0) gave the product 24 (1.23 g, 4.91 mmol, 80%) as
a colorless viscous oil: Rf 0.34 (EtOAc); [R]25D ) +8.2 (c ) 0.18,
MeOH); IR (CHCl3) 3612 (m), 3445 (br s), 1069 (s), 1019 (s)
cm-1 1H NMR (CDCl3, 300 MHz) δ 7.26 (m, 5H), 4.69 (dAB
; ,
1H, J ) 11.7 Hz), 4.45 (dAB, 1H, J ) 11.7 Hz), 3.62 (m, 2H),
3.53 (dd, 1H, J ) 11.1, 6.0 Hz), 3.34 (dd, 1H, J ) 11.1, 6.8
Hz), 2.85 (dd, 1H, J ) 8.3, 3.9 Hz), 2.40 (br s, 1H), 1.99 (m,
1H), 1.58 (br s, 1H), 0.98 (d, 3H, J ) 7.1 Hz), 0.87 (m, 2H),
0.59 (m, 2H); 13C NMR (CDCl3, 75.5 MHz) δ 138.7, 128.4,
127.6(2), 84.9, 70.9, 66.4, 66.0, 39.9, 18.2, 17.3, 12.5, 10.0; MS
(CI, NH3) m/ z 268 [M + NH4]+, 251 [M + H]+, 233 [M - H2O
+ H]+, 191, 160, 143, 130, 125, 108, calcd for C15H23O3 ([M +
H]+) 251.1647, found 251.1662. Anal. Calcd for C15H22O3: C,
71.97; H, 8.86. Found: C, 71.95; H, 8.94.
(1S,3S)-1-[(1S,2R)-2-[(Ch lor om er cu r io)m et h yl]-3-h y-
d r oxy-1-(p h en ylm et h oxy)p r op -1-yl]-3-(h yd r oxym et h yl-
)cyclop r op a n e (21): Rf 0.37 (EtOAc); [R]25D ) +2.8 (c ) 1.51,
MeOH); IR (CHCl3) 3605 (m), 3437 (br s), 1070 (s), 1013 (s)
(1S,3S)-1-[(1S,2R)-1,3-Dih yd r oxy-2-m eth ylp r op -1-yl]-3-
(h yd r oxym eth yl)cyclop r op a n e (25). H2(g) was attached to
a flask containing diol 23 (20.1 mg, 79.9 µmol) and Pd/C (10%,
5.0 mg) in absolute EtOH (0.75 mL), and the mixture was
stirred for 12 h. Chromatography (EtOAc:EtOH 1:0, 1:9) gave
the product 25 (12.6 mg, 78.7 µmol, 98%) as a colorless viscous
cm-1 1H NMR (CDCl3, 300 MHz) δ 7.29 (m, 5H), 4.77 (dAB
; ,
1H, J ) 11.7 Hz), 4.50 (dAB, 1H, J ) 11.7 Hz), 3.89 (dd, 1H, J
) 11.0, 4.9 Hz), 3.56 (m, 2H), 3.41 (dd, 1H, 11.2, 7.0 Hz), 2.83
(dd, 1H, J ) 8.7, 3.5 Hz), 2.27 (m, 1H), 1.77 (dAB, 1H, J ) 12.0,
6.2 Hz), 1.67 (dABd, 1H, J ) 12.0, 5.6 Hz), 1.52 (br s, 2H), 1.17
(m, 1H), 0.83 (m, 1H), 0.44 (dt, 1H, J ) 8.7, 5.1 Hz), 0.32 (dt,
1H, J ) 8.7, 5.3 Hz); 13C NMR (CDCl3, 75.5 MHz) δ 137.8,
128.7, 128.2, 128.1, 84.5, 71.6, 66.0, 64.3, 44.2, 28.2, 21.0, 18.7,
6.4; MS (CI, NH3) m/ z 504 [M + NH4]+, 468 [M - H2O]+, 451
[M - Cl]-, 396, 379, 360, 231, 191, 108, 91, calcd for
C15H25NO3HgCl ([M + NH4]+) 504.1229, found 504.1266.
(1S,3S)-1-[(1R,2R)-2-[(Ch lor om er cu r io)m et h yl]-3-h y-
d r oxy-1-(p h en ylm et h oxy)p r op -1-yl]-3-(h yd r oxym et h yl-
)cyclop r op a n e (22): Rf 0.23 (EtOAc); [R]25D ) -11.7 (c ) 1.06,
MeOH); IR (CHCl3) 3603 (m), 3428 (br s), 1066 (s), 1014 (s)
oil: Rf 0.21 (EtOH:EtOAc ) 1:9); [R]25 ) +10.5 (c ) 2.29,
D
MeOH); IR (film) 3303 (br s), 1088 (s), 1038 (s) cm-1; 1H NMR
(CD3OD, 300 MHz) δ 3.57 (dd, 1H, J ) 10.7, 6.0 Hz), 3.43 (dd,
1H, J ) 10.7, 6.2 Hz), 3.32 (m, 2H), 2.82 (dd, 1H, J ) 8.5, 6.4
Hz), 1.73 (m, 1H), 0.90 (dm, 4H, J ) 7.0 Hz), 0.71 (m, 1H),
0.42 (m, 2H); 13C NMR (CD3OD, 75.5 MHz) δ 76.9, 65.2, 64.7,
42.0, 20.7, 17.8, 12.2, 7.8; MS (CI, NH3) m/ z 178 [M + NH4]+,
160, 143, 130, 125, 112, calcd for C8H20NO3 ([M + NH4]+):
178.1443, found 178.1440.
(1S,3S)-3-(Hyd r oxym eth yl)-1-[(1S,2R)-2-m eth yl-1,3-O-
(1-m et h ylet h ylid en e)-1,3-d ih yd r oxyp r op -1-yl]cyclop r o-
p a n e (26). 2,2-Dimethoxypropane (1 equiv, 25.0 µL, 0.205
mmol) was added to triol 25 (32.9 mg, 0.205 mmol) and
pyridinium p-toluenesulfonate (5.0 mg) in DMF (2 mL) at 0
°C. The mixture was stirred at room temperature for 24 h.
Saturated NaHCO3 solution was added, and the aqueous layer
was extracted into Et2O (5×). The organic layer was washed
with brine and dried (Na2SO4). Rotary evaporation and
chromatography (EtOAc:hexanes 0:1, 1:9, 1:3, 1:1, 3:1, 1:0)
gave the product 26 (24.7 mg, 0.123 mmol, 60%) as a colorless
cm-1 1H NMR (CDCl3, 300 MHz) δ 7.27 (m, 5H), 4.64 (dAB
; ,
1H, J ) 11.8 Hz), 4.45 (dAB, 1H, J ) 11.8), 3.64 (dd, 2H, J )
10.8, 5.5 Hz), 3.52 (dd, 1H, J ) 10.7, 5.8 Hz), 3.32 (dd, 1H, J
) 10.9, 7.2 Hz), 2.93 (dd, 1H, J ) 8.6, 3.4 Hz), 2.35 (m, 1H),
1.97 (dd, 1H, J ) 12.2, 5.2 Hz), 1.71 (dd, 1H, J ) 12.2, 4.4
Hz), 1.57 (br s, 2H), 0.84 (m, 2H), 0.67 (m, 2H); 13C NMR
(CDCl3, 75.5 MHz) δ 137.9, 128.6, 128.1, 128.0, 82.6, 71.2, 66.3,
66.1, 44.6, 25.5, 18.9, 16.8, 11.1; MS (CI, NH3) m/ z 504 [M +
NH4]+, 468 [M - H2O]+, 451 [M - Cl]+, 396, 379, 360, 231,
191, 108, 91, calcd for C15H25NO3HgCl ([M + NH4]+) 504.1229,
found 504.1266.
viscous oil: Rf 0.32 (EtOAc); [R]25 ) +1.8 (c ) 1.06, MeOH);
D
IR (film) 3400 (br s), 1098 (m), 1057 (m), 1011 (m) cm-1; H
1
(1S,3S)-3-(Hydr oxym eth yl)-1-[(1S,2R)-3-h ydr oxy-2-m eth -
yl-1-(p h en ylm eth oxy)p r op -1-yl]cyclop r op a n e (23). Or-
ganomercurial diol 21 (2.48 g, 5.11 mmol) in THF (150 mL)
was added via cannula to LiAlH4 (2.10 g, 55.3 mmol) in THF
(170 mL) at 0 °C under N2. The mixture was stirred at 0 °C
for 3 h and diluted with Et2O, a minimal amount of water and
potassium sodium tartrate were added at 0 °C, and the
mixture was stirred for 30 min. The mixture was filtered
through silica and washed with MeOH/Et2O (1:4). Rotary
evaporation and chromatography (EtOAc:hexanes 0:1, 1:9, 1:3,
1:1, 3:1, 1:0) gave the product 23 (1.10 g, 4.39 mmol, 86%) as
NMR (CDCl3, 300 MHz) δ 3.68 (dd, 1H, J ) 11.7, 5.1 Hz), 3.55
(dd, 1H, J ) 10.9, 6.6 Hz), 3.47 (t, 1H, J ) 11.5 Hz), 3.37 (dd,
1H, J ) 11.0, 7.5 Hz), 2.80 (dd, 1H, J ) 9.8, 8.2 Hz), 2.19 (br
s, 1H), 1.83 (m, 1H), 1.39 (s, 3H), 1.38 (s, 3H), 1.04 (m, 1H),
0.85 (d, 3H, J ) 6.7 Hz), 0.76 (m, 1H), 0.60 (m, 2H); 13C NMR
(CDCl3, 75.5 MHz) δ 98.3, 78.3, 66.4, 66.1, 35.9, 29.8, 20.8,
19.0, 18.0, 12.9, 8.7; MS (CI, NH3) m/ z 218 [M + NH4]+, 201
[M + H]+, 185, 160, 143, 130, 125, 95, calcd for C11H24NO3
([M + NH4]+) 218.17562, found 218.17596; calcd for C11H21O3
([M + H]+) 201.1491, found 201.1493.
a colorless viscous oil: Rf 0.41 (EtOAc); [R]25 ) +16.7 (c )
(1S,3S)-1-[(1R,2R)-1,3-Dih yd r oxy-2-m eth ylp r op -1-yl]-3-
(h yd r oxym eth yl)cyclop r op a n e (27). H2(g) was attached to
a flask containing diol 24 (18.5 mg, 0.0739 mmol) and Pd/C
(10%, 5.0 mg) in absolute EtOH (0.75 mL), and the mixture
was stirred for 12 h. Chromatography (EtOAc:EtOH 1:0, 1:9)
gave the product 27 (11.2 mg, 0.0699 mmol, 95%) as a colorless
D
1.35, MeOH); IR (CHCl3) 3603 (m), 3480 (br s), 1069 (s), 1018
(s) cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.26 (m, 5H), 4.74 (dAB
,
1H, J ) 11.5 Hz), 4.47 (dAB, 1H, J ) 11.5 Hz), 3.71 (dd, 1H, J
) 10.9, 3.9 Hz), 3.55 (dd, 1H, J ) 10.9, 6.0 Hz), 3.49 (dd, 1H,
J ) 11.2, 6.6 Hz), 3.40 (dd, 1H, J ) 11.2, 7.0 Hz), 2.79 (dd,
1H, J ) 8.7, 5.5 Hz), 1.90 (m, 1H), 1.80 (br s, 1H), 1.15 (m,
1H), 0.98 (d, 3H, J ) 7.1 Hz), 0.84 (m, 1H), 0.38 (m, 2H); 13C
NMR (CDCl3, 75.5 MHz) δ 138.4, 128.5, 127.7(2), 86.3, 71.6,
66.3, 66.0, 40.4, 20.4, 19.3, 14.5, 6.9; MS (CI, NH3) m/ z 268
viscous oil: Rf 0.24 (EtOH:EtOAc ) 1:9); [R]25 ) +4.3 (c )
D
0.31, MeOH); IR (film) 3330 (br s), 1088 (s), 1036 (s) cm-1; 1H
NMR (CD3OD, 300 MHz) δ 3.66 (dd, 1H, J ) 10.7, 6.6 Hz),
3.51 (dd, 1H, J ) 10.7, 6.0 Hz), 3.43 (m, 2H), 2.99 (dd, 1H, J

Hg(II)-Mediated Opening of Bi- and Tercyclopropane Arrays
J . Org. Chem., Vol. 62, No. 14, 1997 4661
) 8.4, 4.6 Hz), 1.84 (m, 1H), 1.01 (dm, 4H, J ) 6.9 Hz), 0.94
(m, 1H), 0.58 (m, 1H), 0.48 (m, 1H); 13C NMR (CD3OD, 75.5
MHz) δ 75.9, 64.9, 64.5, 41.5, 20.8, 18.5, 10.9, 7.7; MS (CI,
NH3) m/ z 178 [M + NH4]+, 160, 143, 130, 125, 112, calcd for
C8H20NO3 ([M + NH4]+) 178.1443, found 178.1434.
the product 32 (70.4 mg, 0.281 mmol, 58%) as a colorless
viscous oil: Rf 0.33 (EtOAc); [R]25D ) +24.1 (c ) 0.16, MeOH);
IR (film) 3445 (br s), 1075 (s), 1029 (s) cm-1; 1H NMR (CDCl3,
400 MHz) δ 7.34 (m, 5H), 4.60 (dAB, 1H, J ) 11.5 Hz), 4.48
(dAB, 1H, J ) 11.5 Hz), 3.96 (dd, 1H, J ) 8.7, 6.0 Hz), 3.65 (t,
1H, J ) 4.5 Hz), 3.62-3.57 (m, 3H), 3.49 (dd, 1H, J ) 4.5, 2.3
Hz), 3.12 (m, 1H), 2.34 (m, 1H), 1.88 (m, 1H), 1.10 (d, 3H, J )
7.3 Hz), 0.89 (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3, 100.6 MHz)
δ 137.8, 128.5, 127.8, 127.8, 90.2, 89.7, 73.6, 71.6, 68.0, 39.3,
38.6, 18.2, 13.2; MS (CI, NH3) m/ z 268 [M + NH4]+, 251 [M +
H]+, 118, 108, 91, calcd for C15H23O3 ([M + H]+) 251.1647,
found 251.1642. Anal. Calcd for C15H22O3: C, 71.97; H, 8.86.
Found: C, 71.77; H, 8.70.
(1R*,3S*)-1-(Hydr oxym eth yl)bicyclopr opan e (39). Et2Zn
(neat, 2.10 mL, 20.5 mmol, 6 equiv) was added slowly to
CH2Cl2 (22 mL) when CH2I2 (1.70 mL, 21.1 mmol, 6 equiv)
was added dropwise at -20 °C. The mixture was allowed to
stir for 15 min at -15 °C before a solution of trans-penta-2,4-
dien-1-ol (38)14 (290 mg, 3.45 mmol) in CH2Cl2 (13 mL) was
added via cannula at -20 °C. The mixture was stirred at -10
°C for 2 h and at room temperature for 12 h. The mixture
was quenched with saturated NH4Cl solution at 0 °C followed
by addition of 0.5 M HCl. The product was extracted into
(1S,3S)-3-(Hyd r oxym eth yl)-1-[(1R,2R)-2-m eth yl-1,3-O-
(1-m et h ylet h ylid en e)-1,3-d ih yd r oxyp r op -1-yl]cyclop r o-
p a n e (28). 2,2-Dimethoxypropane (1 equiv, 44.0 µL, 0.362
mmol) was added to triol 27 (58.0 mg, 0.362 mmol) and
pyridinium p-toluenesulfonate (8.0 mg) in DMF (3.5 mL) at 0
°C. The mixture was stirred at room temperture for 24 h.
Saturated NaHCO3 solution was added, and the aqueous layer
was extracted into Et2O (5×). The organic layer was washed
with brine and dried (Na2SO4). Rotary evaporation and
chromatography (EtOAc:hexanes 0:1, 1:9, 1:3, 1:1, 3:1, 1:0)
gave the product 28 (40.6 mg, 0.203 mmol, 56%) as a colorless
viscous oil: Rf 0.39 (EtOAc); [R]25D ) +26.3 (c ) 1.37, MeOH);
1
IR (film) 3401 (br s), 1097 (m), 1058 (m), 1011 (m) cm-1; H
NMR (CDCl3, 300 MHz) δ 4.05 (dd, 1H, J ) 11.5, 2.9 Hz), 3.59
(dd, 1H, J ) 11.5, 1.6 Hz), 3.49 (m, 2H), 3.23 (dd, 1H, J ) 8.2,
2.6 Hz), 1.59 (m, 1H), 1.57 (br s, 1H), 1.42 (s, 3H), 1.39 (s, 3H),
1.19 (d, 3H, J ) 7.0 Hz), 0.93 (m, 1H), 0.88 (m, 1H), 0.60 (m,
2H); 13C NMR (CDCl3, 75.5 MHz) δ 98.6, 75.5, 66.7, 66.4, 32.3,
29.6, 19.4, 19.1, 17.5, 11.5, 9.7; MS (CI, NH3) m/ z 218 [M +
NH4]+, 201 [M + H]+, 185, 160, 143, 130, 125, 95, calcd for
C11H24NO3 ([M + NH4]+): 218.1756, found 218.1750; calcd for
C11H21O3 ([M + H]+) 201.1491, found 201.1491.
CH2Cl2 (4×), and the organic layer was washed with
a
saturated NaHCO3 solution and brine and dried (Na2SO4).
Rotary evaporation at ∼50 mmHg/room temperature and
chromatography (EtOAc:hexanes 0:1, 1:4, 1:1) gave the product
39 (337 mg, 3.01 mmol, 87%) as a colorless oil: Rf 0.25 (Et2O:
(2R,3R,4R)-2-[(1R)-2-Hyd r oxy-1-m eth yleth yl]-4-m eth -
yl-3-(p h en ylm eth oxy)tetr a h yd r ofu r a n (30). Hg(O2CCF3)2
(682 mg, 1.60 mmol, 2 equiv) was added to cyclopropane 23
(195 mg, 0.779 mmol) in CH2Cl2 (8 mL). The mixture was
stirred at room temperature for 48 h, and TLC indicated that
all starting material was consumed. Solid NaCl (5.0 g) was
added, and the mixture was stirred vigorously for 3 h. The
mixture was filtered through silica (washed with EtOAc:
hexanes 0:1, 1:9, 1:3 discarded; EtOAc:hexanes 1:1, 1:0 col-
lected), and rotary evaporation gave crude product 29 (229 mg,
0.472 mmol, 61%). This crude product was dissolved in THF
(28 mL), and LiAlH4 (180 mg, 4.73 mmol) was added at 0 °C
under N2. The mixture was allowed to stir at 0 °C for 3 h and
diluted with Et2O, a minimal amount of water and potassium
sodium tartrate were added at 0 °C, and the solution was
stirred for 30 min. The mixture was filtered through silica
and washed with MeOH/Et2O (1:4). Rotary evaporation and
chromatography (EtOAc:hexanes 0:1, 1:9, 1:4, 1:3, 2:3) gave
the product 30 (64.7 mg, 0.258 mmol, 55%) as a colorless
viscous oil: Rf 0.24 (EtOAc); [R]25D ) -25.8 (c ) 0.59, MeOH);
IR (film) 3447 (br s), 1104 (s), 1042 (s) cm-1; 1H NMR (CDCl3,
400 MHz) δ 7.35 (m, 5H), 4.73 (dAB, 1H, J ) 11.3 Hz), 4.54
(dAB, 1H, J ) 11.3 Hz), 3.94 (t, 1H, J ) 8.0 Hz), 3.86 (t, 1H, J
) 3.5 Hz), 3.70 (dd, 1H, J ) 9.8, 3.1 Hz), 3.62-3.57 (m, 3H),
3.26 (dd, 1H, J ) 7.9, 3.6 Hz), 2.40 (m, 1H), 2.27 (m, 1H), 1.14
(d, 3H, J ) 6.8 Hz), 0.74 (d, 3H, J ) 6.8 Hz); 13C NMR (CDCl3,
100.58 MHz) δ 138.2, 128.4, 127.7, 127.7, 89.6, 81.5, 74.4, 72.9,
68.2, 39.2, 34.6, 13.7, 11.0; MS (CI, NH3) m/ z 268 [M + NH4]+,
251 [M + H]+, 118, 108, 91, calcd for C15H23O3 ([M + H]+)
251.1647, found 251.1640. Anal. Calcd for C15H22O3: C, 71.97;
H, 8.86. Found: C, 71.94; H, 8.81.
(2R,3S,4R)-2-[(1R)-2-Hydr oxy-1-m eth yleth -1-yl]-4-m eth -
yl-3-(p h en ylm eth oxy)tetr a h yd r ofu r a n (32). Hg(O2CCF3)2
(682 mg, 1.60 mmol, 2 equiv) was added to cyclopropane 24
(200 mg, 0.799 mmol) in CH2Cl2 (8 mL). The mixture was
stirred at room temperature for 48 h, and TLC indicated that
all starting material was consumed. Solid NaCl (5.0 g) was
added, and the mixture was stirred vigorously for 3 h. The
mixture was filtered through silica (washed with EtOAc:
hexanes 0:1, 1:9, 1:3 discarded; EtOAc:hexanes 1:1, 1:0 col-
lected), and rotary evaporation gave crude product 31 (235 mg,
0.485 mmol, 61%). This crude product was dissolved in THF
(28 mL), and LiAlH4 (183.1 mg, 4.82 mmol) was added at 0 °C
under N2. The mixture was allowed to stir at 0 °C for 3 h and
diluted with Et2O, a minimal amount of water and potassium
sodium tartrate were added at 0 °C, and the mixtured was
stirred for 30 min. The mixture was filtered through silica
and washed with MeOH/Et2O (1:4). Rotary evaporation and
chromatography (EtOAc:hexanes 0:1, 1:9, 1:4, 1:3, 2:3) gave
hexanes ) 1:1); IR (film) 3446 (br s), 3206 (br s), 1035 (s) cm-1
;
1H NMR (CDCl3, 300 MHz) δ 3.43 (m, 2H), 1.44 (br s, 1H),
0.87 (m, 2H), 0.74 (m, 1H), 0.42-0.30 (m, 4H), 0.06 (m, 2H);
13C NMR (CDCl3, 75.5 MHz) δ 67.09, 19.4, 18.9, 11.89, 8.0,
3.2, 2.9; MS (CI, NH3) m/ z 130 [M + NH4]+, 112, 95, calcd for
C7H16NO ([M + NH4]+) 130.1232, found 130.1231.
Meth yl tr a n s-4-Meth yl-2-p en ten oa te (41). (EtO)2P(O)-
CH2COOMe (23.0 mL, 125 mmol) was added dropwise to
pentane-washed NaH (2.95 g, 123 mmol) in benzene (150 mL),
and the mixture was stirred at room temperature for 45 min.
Isobutyraldehyde (40) (10.0 mL, 110 mmol) was added, and
the mixture was allowed to stir at 70 °C for 2.5 h. After the
reaction was quenched with water (50 mL), the aqueous layer
was extracted with Et2O (4×), and the combined ethers layer
were washed with brine and dried (MgSO4). After removal of
the solvent (at 760 mmHg), the crude product was purified by
distillation (first at 125 °C/760 mmHg to remove trace of the
cis isomer (<100 mg) and at 100 °C/150 mmHg for the trans
isomer) to afford the product 41 as a colorless oil (12.0 g, 86%).
Spectral data were in accord with those reported in the
literature.17
tr a n s-4-Meth yl-2-p en ten -1-ol (42). DIBAL-H (1 M in
hexanes, 140 mL, 140 mmol) was added to ester 41 (6.10 g,
47.6 mmol) in CH2Cl2 (200 mL) at -78 °C. The mixture was
stirred at -78 °C for 1 h and quenched with saturated NH4Cl
solution and 1 M HCl at 0 °C. The aqueous layer was
extracted with CH2Cl2 (4×), and the combined organic layers
were washed with brine and dried (Na2SO4). After removal
of the solvent at ∼80 mmHg/room temperature, the crude
product was purified by distillation (55-65 °C/10-15 mmHg)
to afford the product 42 as a colorless oil (4.70 g, 46.9 mmol,
99%). Spectral data were in accord with those reported in the
literature.18
(1S *,3R *)-1-(H yd r oxym e t h yl)-3-isop r op ylcyclop r o-
p a n e (43). Et2Zn (neat, 6.10 mL, 59.5 mmol, 3 equiv) was
added slowly to CH2Cl2 (80 mL) when CH2I2 (4.80 mL, 59.5
mmol, 3 equiv) was added dropwise at -20 °C. The mixture
was allowed to stir for 15 min at -15 °C before a solution of
42 (2.00 g, 20.0 mmol) in CH2Cl2 (80 mL) was added via
cannula at -20 °C. The mixture was stirred at -20 °C for 2
h and at room temperature for 12 h. The mixture was
quenched with saturated NH4Cl solution at 0 °C followed by
addition of 0.5 M HCl. The product was extracted into CH2Cl2
(17) McGreer, D. E.; Chiu, N. W. K. Can. J . Chem. 1968, 46, 2225.
(18) (a) Gorthey, L. A.; Vairamani, M.; Djerassi, C. J . Org. Chem.
1984, 49, 1511. (b) Piers, E.; J ung, G. L.; Edward, H. Can. J . Chem.
1987, 65, 670.

4662 J . Org. Chem., Vol. 62, No. 14, 1997
Barrett and Tam
(4×), and the organic layer was washed with a saturated
NaHCO3 solution and brine and dried (Na2SO4). Rotary
evaporation at ∼80 mmHg/room temperature and chromatog-
raphy (EtOAc:hexanes 0:1, 1:4, 1:1) gave the product 43 (1.84
g, 16.1 mmol, 81%, containing ∼3% of the cis isomer) as a
colorless oil. Spectral data were in accord with those reported
in the literature.19
The mixture was diluted with Et2O, a minimal amount of
water and potassium sodium tartrate were added at 0 °C, and
the mixture was stirred for 30 min. The product was extracted
into Et2O (×4), and the organic layer was washed with brine
and dried (Na2SO4). Rotary evaporation at ∼80 mmHg/room
temperature and chromatography (EtOAc:hexanes 0:1, 1:9, 1:4,
1:1, 4:1) gave the products 47 (12.4 mg, 0.086 mmol, 65%, dr
∼1.4:1) as a colorless oil: Rf 0.28 (Et2O:hexanes ) 4:1); IR
Mer cu r y-In d u ced Rin g Op en in g of Bicyclop r op a n e 39.
Hg(O2CCF3)2 (380 mg, 0.891 mmol, 2 equiv) was added to
bicyclopropane 39 (50.0 mg, 0.446 mmol) in methanol (4.5 mL).
The mixture was stirred at room temperature for 15 min, and
TLC indicated that all starting material was consumed. After
the solution was stirred for an addition 30 min, solid NaCl
(2.5 g) was added and the mixture was stirred vigorously for
3 h. Excess NaCl was removed by filtration, and the solids
were washed with MeOH/Et2O (1:4). Rotary evaporation and
chromatography (EtOAc:hexanes 0:1, 1:4, 1:1) gave the prod-
ucts 44 (122 mg, 0.321 mmol, 72%, dr ∼2.4:1) and 45 (32.1
mg, 0.085 mmol, 19%, dr ∼1.4:1) both as colorless viscous oils.
(2S*,3R*/S*)-2-[(Ch lor om er cu r io)m eth yl]-3-cyclopr opyl-
3-m eth oxy-1-p r op a n ol (44): Rf 0.34 (EtOAc:hexanes ) 1:1);
IR (film) 3399 (br s), 1086 (s), 1028 (m) cm-1; 1H NMR (CDCl3,
300 MHz) δ 3.94 (dd, 1H, J ) 11.1, 4.5 Hz), 3.57 (m, 1H), 3.39
(s, 3H), 2.42 (dd, 1H, J ) 8.9, 3.1 Hz), 2.32 (m, 1H), 2.15 (br s,
1H), 1.78 (m, 2H), 0.79 (m, 1H), 0.72 (m, 1H), 0.44 (m, 2H),
0.00 (m, 1H); minor isomer showed resolved peaks at δ 3.67
(dd, 1H, J ) 10.7, 5.0 Hz), 3.41 (s, 3H), 2.64 (dd, 1H, J ) 8.6,
3.1 Hz); 13C NMR (CDCl3, 75.5 MHz) δ 89.1, 64.3, 57.7, 43.8,
28.4, 12.1, 5.8, 0.3; minor isomer showed resolved peaks at δ
86.2, 67.1, 56.9, 44.1, 24.2, 12.0, 6.4, -0.2; MS (CI, NH3) m/ z
398 [M + NH4]+, 396 [M + NH4]+, 362, 360, 145, 130, 85, calcd
for C8H19NO2ClHg ([M + NH4]+) 398.0811 and 396.0788, found
398.0813 and 396.0797.
1
(film) 3381 (br s), 1102 (s), 1080 (s), 1052 (s) cm-1; H NMR
(CDCl3, 300 MHz) δ 3.44 (m, 2H), 3.31 (s, 3H), 2.45 (m, 1H),
1.55 (m, 2H), 1.49 (br s, 1H), 0.89 (t, 3H, J ) 7.4 Hz), 0.82 (m,
1H), 0.70-0.27 (m, 3H); minor isomer showed resolved peaks
at δ 3.33 (s, 3H), 1.72 (br s, 1H), 0.88 (t, 3H, J ) 7.5 Hz); 13C
NMR (CDCl3, 75.5 MHz) δ 85.0, 66.5, 56.7, 27.6, 20.2, 17.5,
9.9, 6.6; minor isomer showed resolved peaks at δ 85.3, 56.8,
27.4, 20.4, 9.7, 9.5; MS (CI, NH3) m/ z 162 [M + NH4]+, 145
[M + H]+, 130, 115, 95, 71, calcd for C8H20NO2 ([M + NH4]+)
162.1494, found 162.1494.
(2R*,3S*)-2,4-Dim eth yl-3-m eth oxy-1-p en ta n ol (48). Hg-
(O2CCF3)2 (750 mg, 1.76 mmol, 2 equiv) was added to 43 (100
mg, 0.876 mmol) in MeOH (9 mL). The mixture was stirred
at room temperature and was monitored by TLC. After 10
days, solid NaCl (2.5 g) was added and the mixture was stirred
vigorously for 3 h. Excess NaCl and mercury salts were
removed by filtration through silica (eluted with EtOAc:
hexanes ) 1:1). The residue oil was dissolved in THF (20 mL)
and was added to LiAlH4 (266 mg, 7.00 mmol) in THF (20 mL)
at 0 °C under N2. After being stirred for 3 h at 0 °C, the
mixture was diluted with Et2O, a minimal amount of water
and potassium sodium tartrate were added at 0 °C, and the
mixture was stirred for 30 min. The product was extracted
into Et2O (×5), and the organic layer was washed with brine
and dried (Na2SO4). Rotary evaporation and chromatography
(EtOAc:hexanes 0:1, 1:9, 1:4) gave the product 48 (84.5 mg,
0.587 mmol, 66%) as a colorless oil: Rf 0.21 (EtOAc:hexanes
(1R *,3R *)-1-[3-(Ch lor om e r cu r io)-1(R */S *)-m e t h oxy-
p r op n -1-yl]-3-(h yd r oxym eth yl)cyclop r op a n e (45): Rf 0.18
(EtOAc:hexanes ) 1:1); IR (film) 3399 (br s), 1083 (s), 1041
(s), 1018 (s) cm-1; 1H NMR (CDCl3, 300 MHz) δ 3.48 (m, 2H),
3.37 (s, 3H), 2.48 (m, 1H), 2.10-1.60 (m, 4H), 0.77 (m, 1H),
0.64 (m, 2H), 0.38 (m, 1H); minor isomer showed resolved
peaks at δ 3.40 (s, 3H), 0.25 (m, 1H); 13C NMR (CDCl3, 75.5
MHz) major isomer δ 84.1, 66.2, 56.8, 33.1, 24.4, 19.8, 16.6,
5.7; minor isomer δ 84.2, 66.1, 56.9, 32.8, 24.3, 21.5, 19.7, 10.8;
MS (CI, NH3) m/ z 398 [M + NH4]+, 396 [M + NH4]+, 362,
330, 162, 130, 115, 71, calcd for C8H19NO2ClHg ([M + NH4]+)
398.0811 and 396.0788, found 398.0806 and 396.0786.
(2S*,3R*/S*)-3-Cyclop r op yl-3-m eth oxy-2-m eth yl-1-p r o-
p a n ol (46). LiAlH4 (96.0 mg, 2.53 mmol) was added to 44
(120 mg, 0.317 mmol, dr ∼2.4:1) in THF (15 mL) at 0 °C under
N2, and the mixture was stirred at 0 °C for 3 h. The mixture
was diluted with Et2O, a minimal amount of water and
potassium sodium tartrate were added at 0 °C, and the
mixture was stirred for 30 min. The product was extracted
into Et2O (×4), and the organic layer was washed with brine
and dried (Na2SO4). Rotary evaporation at ∼80 mmHg/room
temperature and chromatography (EtOAc:hexanes 0:1, 1:9, 1:4,
1:1, 4:1) gave the products 46 (30.9 mg, 0.214 mmol, 68%, dr
∼2.4:1) as a colorless oil: Rf 0.43 (Et2O:hexanes ) 4:1); IR
1
) 1:3); IR (film) 3392 (br s), 1087 (s), 1035 (s) cm-1; H NMR
(CDCl3, 300 MHz) δ 3.64 (m, 1H), 3.57 (m, 1H), 3.44 (s, 3H),
2.86 (t, 1H, J ) 5.5 Hz), 2.81 (dd, 1H, J ) 6.3, 5.3 Hz), 1.87-
1.77 (m, 2H), 0.92 (m, 9H); 13C NMR (CDCl3, 75.5 MHz) δ 92.6,
66.3, 61.5, 37.1, 31.0, 20.1, 17.3, 15.5; MS (CI, NH3) m/ z 164
[M + NH4]+, 147 [M + H]+, 99, 87, calcd for C8H19O2 ([M +
H]+) 147.1385, found 147.1385.
(1R*,3S*,4R*,6S*)-1,6-Bis(h yd r oxym eth yl)bicyclop r o-
p a n e (4). TBAF (1 M in THF, contain 5% water) was added
to a solution of 507b,e (201 mg, 0.528 mmol) in THF (0.5 mL)
at room temperature. The mixture was stirred at room
temperature for 2 h and was quenched with MeOH (1 mL).
Rotary evaporation and chromatography (EtOAc:hexanes 1:4,
1:1, 1:0) gave the product 4 (72.8 mg, 0.512 mmol, 97%) as a
colorless oil. Recrystallization from EtOAc at 0 °C afforded
white crystals: mp 29-30 °C; Rf 0.18 (EtOAc); IR (KBr) 3306
1
(br s), 1031 (s), 1015 (s) cm-1; H NMR (CDCl3, 300 MHz) δ
3.48 (m, 2H), 3.35 (m, 2H), 2.12 (br s, 2H), 0.91-0.77 (m, 4H),
0.33 (t, 4H, J ) 6.7 Hz); 13C NMR (CDCl3, 75.47 MHz) δ 66.7,
19.4, 18.1, 8.46; MS (CI, NH3) m/ z 160 [M + NH4]+, 142 [M +
NH4 - H2O]+, 125, 107, 83, calcd for C8H18NO2 ([M + NH4]+)
160.1338, found 160.1341.
(film) 3393 (br s), 1091 (s), 1028 (s) cm-1 1H NMR (CDCl3,
;
Mer cu r y-In d u ced Rin g Op en in g of a n ti-Bicyclop r o-
p a n ed im eth a n ol (4). Hg(O2CCF3)2 (391 mg, 0.917 mmol, 2
equiv) was added to cyclopropanedimethanol 4 (65.0 mg, 0.457
mmol) in BnOH (5 mL). The mixture was stirred at room
temperature for 20 min, and TLC indicated that all starting
material was consumed. Solid NaCl (2.5 g) was added, and
the mixture was stirred vigorously for 3 h. The mixture was
filtered through silica (washed with EtOAc:hexanes 0:1, 1:9,
1:3 discarded; EtOAc:hexanes 1:1, 1:0 collected), and rotary
evaporation gave crude product 51 (166 mg, 0.343 mmol, 75%).
This residue was dissolved in THF (25 mL), and LiAlH4 (180
mg, 4.74 mmol) was added at 0 °C under N2. The mixture
was allowed to stir at 0 °C for 2 h and diluted with Et2O, a
minimal amount of water and potassium sodium tartrate were
added at 0 °C, and the solution was stirred for 30 min. The
mixture was filtered through silica and washed with MeOH/
Et2O (1:4). Rotary evaporation and chromatography (EtOAc:
hexanes 0:1, 1:9, 1:3, 2:3, 4:1, 1:0) gave two combined fractions
(82.4 mg, 72% and 52:53 ∼1:2.2): the first fraction contained
300 MHz) δ 3.61 (m, 1H), 3.46 (m, 1H), 3.313 (s, 3H), 2.84 (t,
1H, J ) 5.4 Hz), 2.38 (dd, 1H, J ) 8.9, 5.9 Hz), 1.83 (m, 1H),
0.89 (d, 3H, J ) 7.1 Hz), 0.76 (m, 1H), 0.54 (m, 1H), 0.37 (m,
1H), 0.28 (m, 1H), 0.00 (m, 1H); minor isomer showed resolved
peaks at δ 3.308 (s, 3H), 2.64 (t, 1H, J ) 5.2 Hz), 2.50 (dd, 1H,
J ) 8.9, 3.2 Hz), 0.88 (d, 3H, J ) 7.1 Hz); 13C NMR (CDCl3,
75.5 MHz) δ 90.3, 66.7, 57.3, 40.3, 14.4, 12.8, 4.2, 1.2; minor
isomer showed resolved peaks at δ 88.7, 57.2, 39.2, 11.7, 11.2,
4.9, 0.3; MS (CI, NH3) m/ z 162 [M + NH4]+, 145 [M + H]+,
130, 112, 95, 85, calcd for C8H20NO2 ([M + NH4]+): 162.1494,
found 162.1490.
(1R*,3R*)-3-(Hydr oxym eth yl)-1-[1(R*/S*)-m eth oxypr op-
1-yl]cyclop r op a n e (47). LiAlH4 (40.0 mg, 1.05 mmol) was
added to 45 (50.2 mg, 0.132 mmol, dr ∼1.4:1) in THF (6 mL)
at 0 °C under N2, and the mixture was stirred at 0 °C for 3 h.
(19) (a) Lillien, I.; Doughty, R. A. J . Org. Chem. 1968, 33, 3841. (b)
Lillien, I.; Handloser, L. J . Am. Chem. Soc. 1971, 93, 1682.

Hg(II)-Mediated Opening of Bi- and Tercyclopropane Arrays
J . Org. Chem., Vol. 62, No. 14, 1997 4663
65% 52, 25% 53, and 10% of nonidentified rearranged products
and the second fraction contained 85% 53 and 15% 52 as
determined by H NMR.
67.2, 66.1, 56.8, 39.7, 37.6, 20.3(2), 16.5, 6.6; MS (CI, NH3)
m/ z 232 [M + NH4]+, 215 [M + H]+, 200, 165, 115, 71, calcd
for C12H26NO3 ([M + NH4]+) 232.1913, found 232.1905. Anal.
Calcd for C12H22O3: C, 67.26; H, 10.35. Found: C, 67.53; H,
10.07.
1
(1S*,3S*)-3-(Hyd r oxym eth yl)-1-[(1S*,2S*)-3-h yd r oxy-2-
m eth yl-1-(p h en ylm eth oxy)p r op -1-yl]cyclop r op a n e (52):
Rf 0.38 (EtOAc); IR (film) 3368 (br s), 1041 (s) cm-1; 1H NMR
(CDCl3, 300 MHz) δ 7.13 (m, 5H), 4.58 (dAB, 1H, J ) 11.8 Hz),
4.37 (dAB, 1H, J ) 11.8 Hz), 3.57-3.23 (m, 4H), 2.79 (dd, 1H,
J ) 8.5, 3.3 Hz), 1.81 (m, 1H), 1.00 (m, 1H), 0.83 (d, 3H, J )
7.2 Hz), 0.69 (m, 1H), 0.27 (m, 1H), 0.19 (m, 1H); 13C NMR
(CDCl3, 75.5 MHz) δ 138.7, 128.5, 127.7, 127.6, 84.2, 71.5, 66.4,
66.2, 39.3, 20.8, 17.9, 11.8, 6.2; MS (CI, NH3) m/ z 268 [M +
NH4]+, 251 [M + H]+, 191, 160, 143, 130, 125, 108, 91, calcd
for C15H23O3 ([M + H]+) 251.1647, found 251.1652.
(1S*,3S*)-3-(Hyd r oxym eth yl)-1-[(1R*,2S*)-3-h yd r oxy-2-
m eth yl-1-(p h en ylm eth oxy)p r op -1-yl]cyclop r op a n e (53):
Rf 0.34 (EtOAc); IR (film) 3368 (br s), 1040 (s) cm-1; 1H NMR
(CDCl3, 300 MHz) δ 7.25 (m, 5H), 4.73 (dAB, 1H, J ) 11.6 Hz),
4.43 (dAB, 1H, J ) 11.6 Hz), 3.72 (dd, 1H, J ) 10.7, 6.8 Hz),
3.63 (m, 2H), 3.24 (dd, 1H, J ) 11.1, 7.6 Hz), 2.74 (dd, 1H, J
) 8.6, 4.7 Hz), 2.47 (br s, 1H), 2.27 (br s, 1H), 1.98 (m, 1H),
0.96 (d, 3H, J ) 7.1Hz), 0.87 (m, 2H), 0.58 (m, 2H); 13C NMR
(CDCl3, 75.5 MHz) δ 138.7, 128.4, 127.6(2), 86.0, 71.2, 66.5,
65.7, 40.1, 19.7, 17.5, 14.6, 10.5; MS (CI, NH3) m/ z 268 [M +
NH4]+, 251 [M + H]+, 233, 191, 160, 143, 125, 95, 91, calcd for
C15H23O3 ([M + H]+) 251.1647, found 251.1653.
Mer cu r y-In d u ced R in g Op en in g of Ter cyclop r o-
p a n ed im eth a n ol 5. Hg(O2CCF3)2 (5.06 g, 11.9 mmol, 3 equiv)
was added to tercyclopropanedimethanol 5 (720 mg, 3.95
mmol) in MeOH (50 mL). The mixture was stirred at room
temperature for 20 min, and TLC indicated that all starting
material was consumed. The mixture was allowed to stir for
an additional 2 h. Solid NaCl (12 g) was added, and the
mixture was stirred vigorously for 3 h. The mixture was
filtered through silica (eluted with EtOAc), and rotary evapo-
ration gave a crude product as a viscous oil. This residue was
filtered through silica again (washed with EtOAc:hexanes 0:1,
1:9, 1:3 discarded; EtOAc:hexanes 1:1, 1:0 collected), and rotary
evaporation gave a gummy white solid residue. The residue
was dissolved in THF (40 mL) and was added via cannula to
a suspension of LiAlH4 (1.50 g, 39.5 mmol, 10 equiv) in THF
(40 mL) at 0 °C under N2. The mixture was allowed to stir at
0 °C for 3 h and diluted with Et2O, a minimal amount of water
and potassium sodium tartrate were added at 0 °C, and the
solution was stirred for 30 min. The mixture was filtered
through silica and washed with MeOH/Et2O (1:5). Rotary
evaporation and chromatography (EtOAc:hexanes 0:1, 1:9, 1:4,
2:3, 3:2, 4:1, 1:0) gave a partially separable mixture of products
60 and 61 both as colorless viscous oils (695 mg, 3.24 mmol,
82%). The first fraction contained 90% 60 and 10% 61, the
second fraction contained 69% 60 and 31% 61, and the third
fraction contained 85% 61 and 15% 60 as determined by 1H
NMR.
(1R,3R)-3-(H yd r oxym e t h yl)-1-[(1R,5R)-6-h yd r oxy-1-
m eth oxy-5-m eth ylh ex-3(E)-en -1-yl]cyclop r op a n e (60): Rf
0.17 (EtOAc); IR (film) 3391 (br s), 1096 (s), 1035 (s) cm-1; 1H
NMR (CDCl3, 400 MHz) δ 5.60 (ddd, 1 H, J ) 15.4, 7.9, 6.7
Hz), 5.33 (dd, 1H, J ) 15.4, 8.1 Hz), 3.62 (dd, 1H, J ) 11.3,
6.0 Hz), 3.51 (dd, 1H, J ) 10.5, 5.0 Hz), 3.37 (s, 3H), 3.32 (dd,
1H, J ) 10.5, 4.7 Hz), 3.27 (dd, 1H, J ) 11.3, 7.5 Hz), 2.60 (dt,
1H, J ) 8.6, 5.5 Hz), 2.42-2.28 (m, 5H), 0.96 (d, 3H, J ) 6.8
Hz), 0.87 (m, 1H), 0.74 (m, 1H), 0.62 (dt, 1H, J ) 8.3, 5.0 Hz),
0.56 (dt, 1H, J ) 8.3, 5.0 Hz); 13C NMR (CDCl3, 100.6 MHz) δ
135.3, 127.6, 83.7, 67.2, 66.1, 56.6, 39.8, 38.0, 20.0, 17.3, 16.5,
9.9; MS (CI, NH3) m/ z 232 [M + NH4]+, 215 [M + H]+, 200,
165, 115, 71, calcd for C12H26NO3 ([M + NH4]+) 232.1913, found
232.1907. Anal. Calcd for C12H22O3: C, 67.26; H, 10.35.
Found: C, 67.37; H, 10.06.
(1R,3R)-3-(Hyd r oxym eth yl)-1-[(1R)-3-h yd r oxy-1-m eth -
oxypr op-1-yl]cyclopr opan e (62). Ozone was passed through
a solution containing diol 60 (200 mg, 0.933 mmol) in MeOH
(0.5 mL) and CH2Cl2 (2.5 mL) at -78 °C. TLC indicated that
all the starting material was consumed in 5 min. NaBH4 (500
mg, 13.2 mmol) was added at -78 °C, and the mixture was
stirred at 0 °C for 1 h and at room temperature for 1 h. The
mixture was quenched with MeOH at 0 °C, a few drops of
water were added, and the mixture was filtered through silica
(MeOH). Rotary evaporation and chromatography (EtOAc:
hexanes 0:1, 1:3, 1:1, 4:1, 1:0, EtOH:EtOAc 1:9) gave the
product 62 (127 mg, 0.794 mmol, 85%) as a colorless viscous
oil: Rf 0.23 (EtOH:EtOAc ) 1:9); [R]25 ) +1.8 (c ) 0.73,
D
MeOH); IR (film) 3353 (br s), 1206 (s), 1142 (s), 1077 (s), 1040
(s), 1016 (s) cm-1; 1H NMR (CDCl3, 300 MHz) δ 3.81 (m, 2H),
3.71 (dd, 1H, J ) 11.3, 5.7 Hz), 3.62 (br s, 2H), 3.39 (s, 3H),
3.18 (dd, 1H, J ) 11.2, 8.1 Hz), 2.72 (m, 1H), 1.88 (m, 2H),
0.84 (m, 2H), 0.65 (m, 2H); 13C NMR (CDCl3, 75.5 MHz) δ 83.7,
66.2, 59.9, 56.6, 36.7, 20.6, 17.0, 10.4; MS (CI, NH3) m/ z 178
[M + NH4]+, 161 [M + H]+, 146, 129, 115, 101, 71, calcd for
C8H17O3 ([M + H]+) 161.1178, found 161.1184. Anal. Calcd
for C8H16O3: C, 59.98; H, 10.07. Found: C, 59.94; H, 10.25.
(1R,3R)-3-(Hyd r oxym eth yl)-1-[(1S)-3-h yd r oxy-1-m eth -
oxypr op-1-yl]cyclopr opan e (64). Ozone was passed through
a solution containing diol 61 (100 mg, 0.467 mmol) in MeOH
(0.25 mL) and CH2Cl2 (1.25 mL) at -78 °C. TLC indicated
that all the starting material was consumed in 5 min. NaBH4
(250 mg, 6.61 mmol) was added at -78 °C, and the mixture
was stirred at 0 °C for 1 h and at room temperature for 1 h.
The mixture was quenched with MeOH at 0 °C, a few drops
of water were added, and the mixture was filtered through
silica (MeOH). Rotary evaporation and chromatography
(EtOAc:hexanes 0:1, 1:3, 1:1, 4:1, 1:0, EtOH:EtOAc 1:9) gave
the product 64 (62.1 mg, 0.388 mmol, 83%) as a colorless
viscous oil: Rf 0.23 (EtOH:EtOAc ) 1:9); [R]25 ) +4.5 (c )
D
0.65, MeOH); IR (film) 3354 (br s), 1206 (s), 1142 (s), 1078 (s),
1041 (s), 1015 (s) cm-1; 1H NMR (CDCl3, 300 MHz) δ 3.76 (m,
2H), 3.56 (dd, 1H, J ) 11.2, 6.5 Hz), 3.43 (s, 3H), 3.40 (m, 1H),
2.92 (br s, 2H), 2.82 (m, 2H), 1.84 (m, 2H), 1.20 (m, 1H), 0.77
(m, 1H), 0.43 (dt, 1H, J ) 8.8, 4.9 Hz), 0.33 (dt, 1H, J ) 8.4,
5.1 Hz); 13C NMR (CDCl3, 75.5 MHz) δ 83.8, 66.0, 60.6, 56.8,
36.7, 21.0, 20.3, 5.9; MS (CI, NH3) m/ z 178 [M + NH4]+, 161
[M + H]+, 146, 129, 115, 101, 71, calcd for C8H17O3 ([M + H]+)
161.1178, found 161.1183.
Mer cu r y-In d u ced In tr a m olecu la r Rin g Op en in g of
Cyclop r op a n e 62. Hg(O2CCF3)2 (546 mg, 1.28 mmol, 2 equiv)
was added to cyclopropane 62 (103 mg, 0.640 mmol) in CH2Cl2
(6.5 mL). The mixture was stirred at room temperature for
48 h, and TLC indicated that all starting material was
consumed. Solid NaCl (4.0 g) was added, and the mixture was
stirred vigorously for 3 h and filtered through silica (EtOAc:
hexanes 0:1, 1:9, 1:3 discarded; EtOAc:hexanes 1:1, 1:0 col-
lected). Rotary evaporation gave a crude product (182 mg,
0.461 mmol, 72%) as a viscous oil which was dissolved in THF
(25 mL), and LiAlH4 (175 mg, 4.61 mmol, 10 equiv) was added
at 0 °C under N2. The mixture was allowed to stir at 0 °C for
3 h and diluted with Et2O, a minimal amount of water and
potassium sodium tartrate were added at 0 °C, and the
solution was stirred for 30 min. The mixture was filtered
through silica and washed with MeOH/Et2O (1:4). Rotary
evaporation and chromatography (EtOAc:hexanes 0:1, 1:9, 1:4,
2:3, 3:2, 4:1, 1:0) gave products 65 (30.5 mg, 0.190 mmol, 41%)
and 66 (23.4 mg, 0.146 mmol, 32%) both as colorless viscous
oils.
(1R ,3R )-3-(H yd r oxym e t h yl)-1-[(1S ,5R )-6-h yd r oxy-1-
m eth oxy-5-m eth ylh ex-3(E)-en -1-yl]cyclop r op a n e (61): Rf
(2S,3R,4R)-2-(Hyd r oxym eth yl)-4-m eth oxy-3-m eth yltet-
0.13 (EtOAc); IR (film) 3370 (br s), 1095 (m), 1033 (s) cm-1
;
r a h yd r op yr a n (65): Rf 0.29 (EtOAc); [R]25D ) -55.4 (c ) 0.50,
1H NMR (CDCl3, 300 MHz) δ 5.56 (dt, 1H, J ) 15.4, 7.0 Hz),
5.34 (dd, 1H, J ) 15.4, 7.4 Hz), 3.51-3.32 (m, 4H), 3.37 (s,
3H), 2.70 (br s, 2H), 2.62 (dt, 1H, J ) 8.3, 5.6 Hz), 2.36-2.27
(m, 3H), 1.12 (m, 1H), 0.97 (d, 3H, J ) 6.8 Hz), 0.73 (m, 1H),
0.37 (m, 2H); 13C NMR (CDCl3, 75.5 MHz) δ 135.1, 127.2, 83.7,
MeOH); IR (film) 3452 (br s), 1095 (s), 1067 (m), 1042 (m) cm-1
;
1H NMR (CDCl3, 400 MHz) δ 4.07 (ddd, 1H, J ) 11.7, 4.9, 1.8
Hz), 3.75 (dd, 1H, J ) 11.6, 2.6 Hz), 3.55 (dd, 1H, J ) 11.6,
6.9 Hz), 3.44 (ddd, 1H, J ) 12.7, 11.7, 2.1 Hz), 3.35 (s, 3H),
3.07 (ddd, 1H, J ) 9.8, 6.9, 2.6 Hz), 2.90 (ddd, 1H, J ) 10.5,

4664 J . Org. Chem., Vol. 62, No. 14, 1997
Barrett and Tam
10.3, 4.6 Hz), 2.24 (br s, 1H), 2.04 (ddt, 1H, J ) 12.8, 4.6, 1.8
Hz), 1.52-1.42 (m, 2H), 0.93 (d, 3H, J ) 6.5 Hz); 13C NMR
(CDCl3, 100.6 MHz) δ 82.0, 81.8, 65.8, 63.8, 56.1, 38.38, 30.9,
12.6; MS (CI, NH3) m/ z 178 [M + NH4]+, 161 [M + H]+, 129,
114, 97, 71, 58, calcd for C8H17O3 ([M + H]+) 161.1178, found
161.1180.
75%) as a colorless viscous oil: Rf 0.31 (EtOAc); [R]25D ) +58.7
(c ) 1.19, MeOH); IR (film) 3447 (br s), 1130 (s), 1067 (s) cm-1
;
1H NMR (CDCl3, 400 MHz) δ 3.98 (dd, 1H, J ) 15.8, 8.2 Hz),
3.82-3.77 (m, 2H), 3.58 (m, 2H), 3.44 (dd, 1H, J ) 9.6, 3.4
Hz), 3.29 (s, 3H), 3.20 (br s, 1H), 2.15 (m, 1H), 2.06 (dddd, 1H,
J ) 13.0, 7.4, 4.1, 1.0 Hz), 1.89 (m, 1H), 0.83 (d, 3H, J ) 6.8
Hz); 13C NMR (CDCl3, 100.6 MHz) δ 88.1, 80.7, 68.1, 66.5, 56.6,
34.4, 30.2, 13.5; MS (CI, NH3) m/ z 178 [M + NH4]+, 161 [M +
H]+, 128, 101, 72, calcd for C8H17O3 ([M + H]+) 161.1178, found
161.1174.
(2S,3R)-2-[(1S)-2-Hyd r oxy-1-m eth yleth -1-yl]-3-m eth ox-
ytetr a h yd r ofu r a n (66): Rf 0.34 (EtOAc); [R]25 ) -66.9 (c
D
) 0.34, MeOH); IR (film) 3434 (br s), 1113 (s), 1065 (s) cm-1
;
1H NMR (CDCl3, 400 MHz) δ 3.96 (ddd, 1H, J ) 8.4, 7.2, 4.1
Hz), 3.82 (dd, 1H, J ) 15.7, 8.4 Hz), 3.71 (dt, 1H, J ) 5.4, 3.3
Hz), 3.65-3.60 (m, 3H), 3.32 (s, 3H), 3.18 (br s, 1H), 1.96 (m,
2H), 1.73 (m, 1H), 0.90 (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3,
100.6 MHz) δ 89.2, 84.4, 67.7, 66.9, 56.7, 38.2, 31.4, 13.3; MS
(CI, NH3) m/ z 178 [M + NH4]+, 161 [M + H]+, 128, 101, 72,
calcd for C8H17O3 ([M + H]+) 161.1178, found 161.1169.
(2S,3S)-2-[(1S)-2-Hyd r oxy-1-m eth yleth -1-yl]-3-m eth ox-
ytetr a h yd r ofu r a n (67). Hg(O2CCF3)2 (268 mg, 0.628 mmol,
2 equiv) was added to cyclopropane 64 (50.3 mg, 0.314 mmol)
in CH2Cl2 (3 mL). The mixture was stirred at room temper-
ature for 48 h, and TLC indicated that all starting material
was consumed. Solid NaCl (2.0 g) was added, the mixture was
stirred vigorously for 3 h and filtered through silica (EtOAc:
hexanes 0:1, 1:9, 1:3 discarded; EtOAc:hexanes 1:1, 1:0 col-
lected). Rotary evaporation gave a crude product (95.5 mg,
0.242 mmol, 77%) as a viscous oil which was dissolved in THF
(13 mL), and LiAlH4 (92.8 mg, 2.44 mmol, 10 equiv) was added
at 0 °C under N2. The mixture was allowed to stir at 0 °C for
3 h and diluted with Et2O, a minimal amount of water and
potassium sodium tartrate were added at 0 °C, and the
solution was stirred for 30 min. The mixture was filtered
through silica and washed with MeOH/Et2O (1:4). Rotary
evaporation and chromatography (EtOAc:hexanes 0:1, 1:9, 1:4,
2:3, 3:2, 4:1, 1:0) gave the product 67 (29.1 mg, 0.182 mmol,
Ack n ow led gm en t. We thank Glaxo Group Re-
search Ltd. for
a most generous endowment (to
A.G.M.B.), the Wolfson Foundation for establishing the
Wolfson Centre for Organic Chemistry in Medical
Science at Imperial College, the Engineering and Physi-
cal Science Research Council, Millennium Pharmaceuti-
cal Inc. for support of our research on antifungal agents,
G.D. Searle & Company for generous unrestricted
support, the Natural Science and Engineering Research
Council (NSERC) of Canada for a postdoctoral fellow-
ship (to W.T.), and Dr. Dieter Hamprecht for helpful
discussion.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 4, 19-28, 30, 32, 39, 44-48, 52, 53, 60-62, and
64-67 (34 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 ACS; see any
current masthead page for ordering information.
J O970464O